Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists

ABSTRACT

This invention relates to compounds that are agonists of the muscarinic M 1  receptor or M 1  and M 4  receptors and which are useful in the treatment of muscarinic M 1  or M 1 /M 4  receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula 
                         
wherein Q 4 , Q 5 , R 5 , p, V, Q 1 , Q 2 , X 1 , X 2  and W are defined herein.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. patent application Ser. No.16/295,364, filed Mar. 7, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/784,560, filed Oct. 16, 2017, now U.S. Pat. No.10,259,787, which claims the benefit of U.S. Provisional Application No.62/408,468, filed on Oct. 14, 2016. The entire contents of theseapplications are incorporated herein by reference in their entirety.

This invention relates to compounds that are agonists of the muscarinicM₁ receptor or the M₁ and M₄ receptors and which are useful in thetreatment of muscarinic M₁ or M₁ and M₄ receptor mediated diseases. Alsoprovided are pharmaceutical compositions containing the compounds andthe therapeutic uses of the compounds.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse et al., 1982 Science). In schizophrenia, whichalso has cognitive impairment as an important component of the clinicalpicture, mAChR density is reduced in the pre-frontal cortex, hippocampusand caudate putamen of schizophrenic subjects (Dean et al., 2002 MolPsychiatry).

Furthermore, in animal models, blockade or damage to central cholinergicpathways results in profound cognitive deficits and non-selective mAChRantagonists have been shown to induce psychotomimetic effects inpsychiatric patients. Cholinergic replacement therapy has largely beenbased on the use of acetylcholinesterase inhibitors to prevent thebreakdown of endogenous acetylcholine. These compounds have shownefficacy versus symptomatic cognitive decline in the clinic, but giverise to dose-limiting adverse events resulting from stimulation ofperipheral M₂ and M₃ mAChRs including disturbed gastrointestinalmotility, bradycardia, nausea and vomiting(www.drugs.com/pro/donepezil.html; www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists with the aim of inducing selective improvements incognitive function with a favourable adverse effect profile. Suchefforts resulted in the identification of a range of agonists,exemplified by compounds such as xanomeline, AF267B, sabcomeline,milameline and cevimeline. Many of these compounds have been shown to behighly effective in pre-clinical models of cognition in both rodentsand/or non-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain pathologies: aggregates of amyloid plaques, largelycomposed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formedby hyperphosphorylated tau proteins. The accumulation of Aβ is thoughtto be the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. Aβ is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, nonamyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. However, in the amyloidgenicroute, APP is cleaved by β-secretase to yield soluble APPβ and also Aβ.In vitro studies have shown that mAChR agonists can promote theprocessing of APP toward the soluble, non-amyloidogenic pathway. In vivostudies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron). ThemAChR agonist cevimeline has been shown to give a small, butsignificant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Preclinical studies have suggested that mAChR agonists display anatypical antipsychotic-like profile in a range of pre-clinicalparadigms. The mAChR agonist, xanomeline, reverses a number of dopaminemediated behaviours, including amphetamine induced locomotion in rats,apomorphine induced climbing in mice, dopamine agonist driven turning inunilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest inmonkeys (without EPS liability). It also has been shown to inhibit A10,but not A9, dopamine cell firing and conditioned avoidance and inducesc-fos expression in prefrontal cortex and nucleus accumbens, but not instriatum in rats. These data are all suggestive of an atypicalantipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev).

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic adverse events, including nausea, gastrointestinal pain,diahorrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damage;however management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M₁ receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Let Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al., 2010ACS Med Chem Lett). Despite increased levels of selectivity versus theM₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ mAChR over the M₂ and M₃ receptor subtypes.

THE INVENTION

The present invention provides compounds having activity as muscarinicM₁ and/or M₄ receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M₁ receptor relativeto the M₂, M₃ and M₄ receptor subtypes. Alternative compounds of theinvention exhibit selectivity for the M₁ and M₄ receptors relative tothe M₂ and M₃ receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1):

or a salt thereof, wherein:

p is 0, 1 or 2;

V is selected from a bond, NH, N(C₁₋₃alkyl), NH—CH₂ and N(C₁₋₃alkyl)-CH₂;

Q¹ and Q² are each nitrogen or carbon; provided that at least one of Q′or V comprises a nitrogen atom;

W is -Q³C(O)YCH₂R⁴ or an optionally substituted five or six memberedaromatic heterocyclic group, wherein when W is an optionally substitutedfive or six membered aromatic heterocyclic group, Q² is carbon;

Q³ is a bond or a group -(Alk)_(q)-NR⁶ where Alk is an alkyl group of 1to 4 carbon atoms;

q is 0 or 1; and R⁶ is hydrogen or a saturated C₁₋₄ hydrocarbon group;provided that when Q² is nitrogen and Q³ is a group -(Alk)_(q)-NR⁶,there are at least two carbon atoms in line between Q² and NR⁶ andprovided that when Q³ is a bond, Q² is nitrogen;

X¹ and X² are optionally substituted saturated hydrocarbon groups whichtogether contain a total of one to nine carbon atoms and which linktogether such that the moiety:

forms a monocyclic or bicyclic ring system;

Q⁴ is an optionally substituted five or six membered aromaticcarbocyclic or heterocyclic group containing 0, 1, 2 or 3 heteroatomring members selected from O, N and S, or forms an optionallysubstituted heterocyclic spirocyclic ring with Q⁵;

Q⁵ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof, or formsan optionally substituted heterocyclic spirocyclic ring with Q⁴; Y is CHor O;

R⁴ is hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof; and

R⁵ is fluorine or a C₁₋₄ hydrocarbon group.

Particular compounds of the formula (1) are as defined in theEmbodiments 1.2 to 1.168 set out below.

1.2 A compound according to Embodiment 1.1 wherein Q⁴ is an optionallysubstituted five or six membered aromatic carbocyclic or heterocyclicgroup selected from optionally substituted phenyl; optionallysubstituted six membered aromatic heterocyclic rings containing 1, 2 or3 nitrogen ring members; and optionally substituted five memberedaromatic heterocyclic rings containing 1, 2 or 3 heteroatom ring membersselected from O, N and S.

1.3 A compound according to Embodiment 1.2 wherein Q⁴ is an optionallysubstituted five or six membered aromatic carbocyclic or heterocyclicgroup selected from optionally substituted phenyl; optionallysubstituted six membered aromatic heterocyclic rings containing 1 or 2nitrogen ring members; and optionally substituted five membered aromaticheterocyclic rings containing 1 or 2 heteroatom ring members selectedfrom O, N and S.

1.4 A compound according to Embodiment 1.3 wherein Q⁴ is an optionallysubstituted five or six membered aromatic carbocyclic or heterocyclicgroup selected from optionally substituted phenyl; optionallysubstituted six membered aromatic heterocyclic rings containing 1nitrogen ring member; and optionally substituted five membered aromaticheterocyclic rings containing 1 or 2 heteroatom ring members selectedfrom O, N and S.

1.5 A compound according to Embodiment 1.4 wherein Q⁴ is an optionallysubstituted five or six membered aromatic carbocyclic or heterocyclicgroup selected from optionally substituted phenyl; optionallysubstituted pyridyl; optionally substituted imidazolyl; and optionallysubstituted thienyl.

1.6 A compound according to Embodiment 1.5 wherein Q⁴ is an optionallysubstituted phenyl or pyridyl group.

1.7 A compound according to any one of Embodiments 1.1 to 1.6 whereinthe five or six membered aromatic carbocyclic or heterocyclic group Q⁴is unsubstituted or is substituted with one or more substituents Q⁶selected from halogen; cyano; hydroxy; amino and a C₁₋₁₀ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one, two or three, but not all, carbon atomsof the hydrocarbon group may optionally be replaced by a heteroatomselected from O, N and S and oxidized forms thereof.

1.8 A compound according to Embodiment 1.7 wherein the five or sixmembered aromatic carbocyclic or heterocyclic group Q⁴ is unsubstitutedor is substituted with one or more substituents Q⁶ selected fromhalogen; cyano; hydroxy; amino and a C₁₋₁₀ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one carbon atom of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S or oxidized formsthereof, or two adjacent carbon atoms of the hydrocarbon group mayoptionally be replaced by a group X³C(X⁴) or C(X⁴)X³ where X³ is O, S orN; and X⁴ is ═O, ═S or ═N.

1.9 A compound according to Embodiment 1.8 wherein the five or sixmembered aromatic carbocyclic or heterocyclic group Q⁴ is unsubstitutedor is substituted with one or more substituents Cr selected fromhalogen; cyano; hydroxy; amino and a C₁₋₁₀ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one carbon atom of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S thereof, or twoadjacent carbon atoms of the hydrocarbon group may optionally bereplaced by a group OC(═O), C(═O)O, N(C═O) or C(═O)N.

1.10 A compound according to Embodiment 1.9 wherein the five or sixmembered aromatic carbocyclic or heterocyclic group Q⁴ is unsubstitutedor is substituted with one or more substituents Q⁶ selected fromhalogen; cyano; hydroxy; amino and a C₁₋₈ non-aromatic hydrocarbon groupwhich is optionally substituted with one to six fluorine atoms andwherein one carbon atom of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S thereof, or twoadjacent carbon atoms of the hydrocarbon group may optionally bereplaced by a group OC(═O), C(═O)O, N(C═O) or C(═O)N.

1.11 A compound according to Embodiment 1.9 wherein the five or sixmembered aromatic carbocyclic or heterocyclic group Q⁴ is unsubstitutedor is substituted with one or more substituents Q⁶ selected fromhalogen; cyano; hydroxy; amino and a C₁₋₆ non-aromatic hydrocarbon groupwhich is optionally substituted with one to six fluorine atoms andwherein one carbon atom of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S thereof, or twoadjacent carbon atoms of the hydrocarbon group may optionally bereplaced by a group OC(═O), C(═O)O, N(C═O) or C(═O)N.

1.12 A compound according to Embodiment 1.7 wherein the optionallysubstituted non-aromatic hydrocarbon group is selected from C₁₋₅ alkyl;C₂₋₅ alkenyl; C₂₋₅ alkynyl; C₃₋₆ cycloalkyl and C₄₋₆ cycloalkenylgroups; and each of the said alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups is optionally substituted with one to six fluorineatoms and wherein one or two, but not all, carbon atoms of each of thealkyl, alkenyl, alkynyl, cycloakyl and cycloalkenyl groups mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof.

1.13 A compound according to any one of Embodiments 1.1 to 1.6 whereinQ⁴ is an unsubstituted five or six membered aromatic carbocyclic orheterocyclic group.

1.14 A compound according to Embodiment 1.13 wherein Q⁴ is anunsubstituted phenyl or pyridyl group.

1.15 A compound according to any one of Embodiments 1.1 to 1.14 whereinQ⁵ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₆ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one or two, but not all, carbonatoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof.

1.16 A compound according to Embodiment 1.15 wherein Q⁵ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; and a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof.

1.17 A compound according to Embodiment 1.16 wherein Q⁵ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; C₁₋₄ alkyl and C₁₋₄ alkoxy,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith one to six fluorine atoms.

1.18 A compound according to Embodiment 1.17 wherein Q⁵ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; methyl, ethyl and methoxy.

1.19 A compound according to Embodiment 1.18 wherein Q⁵ is cyano.

1.20 A compound according to Embodiment 1.1 wherein Q⁴ and Q⁵ form aheterocyclic spirocyclic ring according to formula (1a):

wherein Z is C or N;

R¹ is H, COOR⁷, CONR⁷R⁸, SO₂R⁷ or an optionally substituted C₁₋₆non-aromatic hydrocarbon group where one or more carbon atoms isoptionally replaced with a heteratom selected from O, N or S;

R² and R^(2a) are independently selected from hydrogen; halogen; cyano;hydroxy; amino; and a C1-4 non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof;

R³ is selected from hydrogen or oxo;

R⁷ and R⁸ are independently H or a C₁₋₄ hydrocarbon group.

1.21 A compound according to Embodiment 1.20 wherein R¹ is H, COOR⁷,CONR⁷R⁸, SO₂R⁷ or an optionally substituted C₁₋₆alkyl group.

1.22 A compound according to Embodiment 1.21 wherein R¹ is an optionallysubstituted alkyl group selected from CH₂—COOR⁷, CH₂—CONR⁷R⁷, CH₂—SO₂R⁷CH₂—CH₂—COOR⁷, CH₂—CH₂—CONR⁷R⁸ or CH₂—CH₂—SO₂R⁷.

1.23 A compound according to Embodiment 1.22 wherein R¹ is H, methyl,ethyl, COOCH₃, COOCH₂CH₃, SO₂Me or CH₂CONH₂.

1.24 A compound according to Embodiment 1.23 wherein R¹ is H.

1.25 A compound according to Embodiment 1.23 wherein R¹ is methyl.

1.26 A compound according to Embodiment 1.23 wherein R¹ is SO₂Me.

1.27 A compound according to Embodiment 1.23 wherein R¹ is CH₂CONH₂.

1.28 A compound according to Embodiment 1.23 wherein R¹ is COOCH₂CH₃.

1.29 A compound according to any one of Embodiments 1.20 to 1.28 whereinR² and R^(2a) are independently selected from hydrogen; fluorine;chlorine; cyano; hydroxy; amino; and a C₁₋₄ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof.

1.30 A compound according to Embodiment 1.29 wherein R² and R^(2a) areindependently selected from hydrogen; fluorine; chlorine; cyano;hydroxy; amino; and a C₁₋₄ alkyl or C₁₋₄ alkoxy group which isoptionally substituted with one to six fluorine atoms.

1.31 A compound according to Embodiment 1.30 wherein R² and R^(2a) areindependently selected from hydrogen; fluorine; chlorine; cyano;hydroxy; amino; methyl, ethyl, methoxy trifluoromethoxy or ethoxy.

1.32 A compound according to Embodiment 1.31 wherein R² and R^(2a) areindependently selected from hydrogen; fluorine; chlorine; cyano; methylor methoxy.

1.33 A compound according to any one of Embodiments 1.20 to 1.32 whereinR³ is H such that the ring position marked R₃ is CH₂.

1.34 A compound according to any one of Embodiments 1.20 to 1.32 whereinR³ is oxo such that the ring position marked R₃ is C═O.

1.35 A compound according to Embodiments 1.34 wherein Z is C.

1.36 A compound according to any one of Embodiments 1.1 to 1.35 whereinp is 0 or 1.

1.37 A compound according to Embodiment 1.36 wherein p is O.

1.38 A compound according to Embodiment 1.36 wherein p is 1.

1.39 A compound according to any one of Embodiments 1.1 to 1.38 whereinp is 0; or p is 1 and R⁵ is selected from fluorine and a saturated C₁₋₄hydrocarbon group.

1.40 A compound according to Embodiment 1.39 wherein p is 0; or p is 1and R⁵ is selected from fluorine, C₁₋₃ alkyl and cyclopropyl.

1.41 A compound according to Embodiment 1.39 wherein p is 0; or p is 1and R⁵ is selected from fluorine and methyl.

1.42 A compound according to Embodiment 1.41 wherein p is 0; or p is 1and R⁵ is fluorine.

1.43 A compound according to any one of Embodiments 1.1 to 1.42 whereinwherein V is a bond

1.44 A compound according to Embodiment 1.43 wherein V is a bond and Q¹is nitrogen.

1.45 A compound according to any one of Embodiments 1.1 to 1.42 whereinwherein V is selected from NH, N(C₁₋₃alkyl), NH—CH₂ and N(C₁₋₃alkyl)-CH₂.

1.46 A compound according to any one of Embodiments 1.1 to 1.42 whereinV is NH.

1.47 A compound according to any one of Embodiments 1.1 to 1.42 whereinV is NH—CH₂.

1.48 A compound according to any one of Embodiments 1.1 to 1.42 whereinV is N(C₁₋₃ alkyl).

1.49 A compound according to any one of Embodiments 1.1 to 1.42 whereinV is N(C₁₋₃ alkyl)-CH₂.

1.50 A compound according to one of Embodiments 1.1 to 1.49 wherein W isan optionally substituted five or six membered heteroaryl group. When Wis an optionally substituted five or six membered heteroaryl group, Q²is carbon.

1.51 A compound according to Embodiment 1.50 wherein W is optionallysubstituted 1-oxa-2,4-diazole.

1.52 A compound according to Embodiments 1.50 or 1.51 wherein theheteroaryl group W is optionally substituted with C₁₋₄ hydrocarbon groupwhich is itself optionally substituted with one to six fluorine atoms.

1.53 A compound according to Embodiment 1.52 wherein the heteroarylgroup W is optionally substituted with methyl, ethyl or trifluoromethyl.

1.54 A compound according to Embodiment 1.53 wherein W is selected fromgroups W1 to W3 shown below:

where “a” indicates the point of attachment to Q².

1.55 A compound according to any Embodiments 1.1 to 1.42 wherein W is-Q³C(O)YCH₂R⁴.

1.56 A compound according to Embodiment 1.55 wherein Y is O.

1.57 A compound according to Embodiment 1.55 wherein Y is CH.

1.58 A compound according to Embodiment 1.57 wherein Y is CH and R⁴ isCH—CH₃ such that Y—R⁴ is CH═CH—CH₃.

1.59 A compound according to any one of Embodiments 1.1 to 1.58 whereinR⁴ is hydrogen or an acyclic C₁₋₆ hydrocarbon group.

1.60 A compound according to Embodiment 1.59 wherein R⁴ is hydrogen oran acyclic C₁₋₃ hydrocarbon group.

1.61 A compound according to Embodiment 1.60 wherein R⁴ is a C₁₋₃ alkylgroup or a C₂₋₃ alkynyl group.

1.62 A compound according to Embodiment 1.61 wherein R⁴ is selected fromH, methyl, ethyl, ethynyl and 1-propynyl.

1.63 A compound according to Embodiment 1.62 wherein Y—R⁴ is O-ethyl,O-methyl or CH═CH—CH₃.

1.64 A compound according to any one of Embodiments 1.1 to 1.63 whereinX¹ and X² together contain one, two, three, four, five, six, seven,eight or nine carbon atoms, which may be optionally substituted withsubstituents selected from hydrogen, fluorine, hydroxy, methyl, ethyland methoxy. Where X¹ and X² together contain four carbon atoms, thegroup may optionally not include 1-4 piperidine, which can be disclaimedfrom any particular claim if required.

1.65 A compound according to Embodiment 1.64 wherein X¹ and X² togethercontain five carbon atoms.

1.66 A compound according to Embodiment 1.64 wherein X¹ and X² togethercontain six carbon atoms.

1.67 A compound according to Embodiment 1.64 wherein X¹ and X² togethercontain seven carbon atoms.

1.68 A compound according to any one of Embodiments 1.45 to 1.64 whereinV is selected from NH, N(C₁₋₃alkyl), NH—CH₂ and N(C₁₋₃ alkyl)-CH₂ and Q¹and Q² each represent carbon.

1.69 A compound according to any one of Embodiments 1.45 to 1.64 whereinV is NH or NHCH₂ and Q¹ and Q² each represent carbon.

1.70 A compound according to Embodiments 1.43 or 1.44 wherein Q¹ and Q²are both nitrogen and Q³ is a bond; or Q¹ is nitrogen, Q² is carbon andQ³ is a group -(Alk)_(q)-NR⁶.

1.71 A compound according to Embodiment 1.70 wherein Q¹ and Q² are bothnitrogen and Q³ is a bond.

1.72 A compound according to Embodiment 1.70 wherein Q¹ is nitrogen, Q²is carbon and Q³ is a group -(Alk)_(q)-NR⁶.

1.73 A compound according to Embodiment 1.71 wherein Q¹ and Q² togetherwith X¹ and X² form a bicyclic group, an optionally substituteddiazepane group or a diazocane group.

1.74 A compound according to Embodiment 1.73 wherein Q¹ and Q² togetherwith X¹ and X² form a diazocane group.

1.75 A compound according to Embodiment 1.74 wherein the diazocane groupis a 1,5-diazocane group.

1.76 A compound according to Embodiment 1.73 wherein Q¹ and Q² togetherwith X¹ and X² form an optionally substituted diazepane group.

1.77 A compound according to Embodiment 1.74 wherein the optionallysubstituted diazepane group is a 1,4-diazepane group.

1.78 A compound according to any of Embodiments 1.76 or 1.77 wherein thediazepane group is optionally substituted with halogen or hydroxy.

1.79 A compound according to Embodiment 1.73 wherein Q¹ and Q² togetherwith X¹ and X² form a bicyclic group.

1.80 A compound according to Embodiment 1.79 wherein the bicyclic groupis a fused bicyclic group.

1.81 A compound according to Embodiment 1.79 wherein the bicyclic groupis a spirocyclic bicyclic group.

1.82 A compound according to Embodiment 1.79 wherein the bicyclic groupis selected from a [4.2.0] fused bicyclic group, a [4.3.0] fusedbicyclic group, a [3.3.0] fused bicyclic group, a [4.5] spirocyclicbicyclic group, a [3.4] spirocyclic bicyclic group and a [3.5]spirocyclic bicyclic group.

1.83 A compound according to Embodiment 1.82 wherein the bicyclic groupis selected from a [4.2.0] fused bicyclic group, a [4.3.0] fusedbicyclic group and a [3.3.0] fused bicyclic group.

1.84 A compound according to Embodiment 1.83 wherein the bicyclic groupis a [4.2.0] fused bicyclic group.

1.85 A compound according to Embodiment 1.84 wherein the [4.2.0] fusedbicyclic group is a diazabicyclo[4.2.0]octane group.

1.86 A compound according to Embodiment 1.82 wherein the bicyclic groupis a [3.3.0] fused bicyclic group.

1.87 A compound according to Embodiment 1.86 wherein the [3.3.0] fusedbicyclic group is a hexahydropyrrolo[3,4-b]pyrrole group.

1.88 A compound according to Embodiment 1.82 wherein the bicyclic groupis a [4.3.0] fused bicyclic group.

1.89 A compound according to Embodiment 1.88 wherein the [4.3.0] fusedbicyclic group is a octahydro-6H-pyrrolo[3,4-b]pyridine group.

1.90 A compound according to Embodiment 1.82 wherein the spirocyclicbicyclic group is a [3.4] spirocyclic bicyclic group.

1.91 A compound according to Embodiment 1.90 wherein the [3.4]spirocyclic bicyclic group is a 2,6-diazaspiro[3.4]octane group.

1.92 A compound according to Embodiment 1.78 wherein the spirocyclicbicyclic group is a [3.5] spirocyclic bicyclic group.

1.93 A compound according to Embodiment 1.92 wherein the [3.5]spirocyclic bicyclic group is a 2,7-diazaspiro[3.5]nonane group.

1.94 A compound according to Embodiment 1.78 wherein the spirocyclicbicyclic group is a [4.5] spirocyclic bicyclic group.

1.95 A compound according to Embodiment 1.91 wherein the [4.5]spirocyclic bicyclic group is a 2,8-diazaspiro[4.5]decane group.

1.96 A compound according to Embodiment 1.72 wherein Q¹ and Q² togetherwith X¹ and X² form a monocyclic group.

1.97 A compound according to Embodiment 1.96 wherein the monocyclicgroup is pyrolidine or piperidine or diazepane group.

1.98 A compound according to Embodiment 1.97 wherein the piperidinegroup is a piperidine-1,4-diyl group.

1.99 A compound according to Embodiment 1.97 wherein the piperidinegroup is a piperidine-1,3-diyl group.

1.100 A compound according to Embodiment 1.97 wherein the pyrolidinegroup is a pyrolidine-1,3-diyl group.

1.101 A compound according to Embodiment 1.72 wherein Q¹ and Q² togetherwith X¹ and X² form a bicyclic group.

1.102 A compound according to Embodiment 1.101 wherein the bicyclicgroup is a fused bicyclic group.

1.103 A compound according to Embodiment 1.101 wherein the bicyclicgroup is a spirocyclic bicyclic group.

1.104 A compound according to Embodiment 1.101 wherein the bicyclicgroup is a bridged bicyclic group.

1.105 A compound according to Embodiment 1.101 wherein the bicyclicgroup is selected from a [3.1.0] fused bicyclic group, a [2.2.1] bridgedbicyclic group, a [2.2.2] bridged bicyclic group, a [3.4] spirocyclicbicyclic group, a [3.3] spirocyclic bicyclic group and a [2.3]spirocyclic bicyclic group.

1.106 A compound according to Embodiment 1.105 wherein the bicyclicgroup is a [3.1.0] fused bicyclic group.

1.107 A compound according to Embodiment 1.106 wherein the [3.1.0] fusedbicyclic group is an azabicyclo[3.1.0]hexane group.

1.108 A compound according to Embodiment 1.105 wherein the bicyclicgroup is selected from a [2.2.1] bridged bicyclic group, a [2.2.2]bridged bicyclic group.

1.109 A compound according to Embodiment 1.108 wherein the bicyclicgroup is a [2.2.1] bridged bicyclic group.

1.110 A compound according to Embodiment 1.109 wherein the [2.2.1]bridged bicyclic group is an azabicyclo[2.2.1]heptane group.

1.111 A compound according to Embodiment 1.108 wherein the bicyclicgroup is a [2.2.2] bridged bicyclic group.

1.112 A compound according to Embodiment 1.111 wherein the [2.2.2]bridged bicyclic group is an azabicyclo[2.2.2]octane group.

1.113 A compound according to Embodiment 1.105 wherein the bicyclicgroup is selected from a [3.4] spirocyclic bicyclic group, a [3.3]spirocyclic bicyclic group and a [2.3] spirocyclic bicyclic group.

1.114 A compound according to Embodiment 1.113 wherein the spirocyclicbicyclic group is a [3.4] spirocyclic bicyclic group.

1.115 A compound according to Embodiment 1.114 wherein the [3.4]spirocyclic bicyclic group is a 7-azaspiro[3.4]octane group.

1.116 A compound according to Embodiment 1.113 wherein the spirocyclicbicyclic group is a [3.3] spirocyclic bicyclic group.

1.117 A compound according to Embodiment 1.116 wherein the [3.3]spirocyclic bicyclic group is a 6-azaspiro[3.3]heptane group.

1.118 A compound according to Embodiment 1.113 wherein the spirocyclicbicyclic group is a [2.3] spirocyclic bicyclic group.

1.119 A compound according to Embodiment 1.118 wherein the [2.3]spirocyclic bicyclic group is a 5-azaspiro[2.3]hexane group.

1.120 A compound according to any one of Embodiments 1.96 to 1.119wherein q is 1.

1.121 A compound according to Embodiment 1.120 wherein Alk is a CH₂group.

1.122 A compound according to any one of Embodiments 1.96 to 1.119wherein q is 0.

1.123 A compound according to any one of Embodiments 1.96 to 1.119wherein R⁶ is hydrogen or a C₁₋₄ alkyl group.

1.124 A compound according to Embodiment 1.123 wherein R⁶ is hydrogen ora C₁₋₂ alkyl group.

1.125 A compound according to Embodiment 1.124 wherein R⁶ is hydrogen ora methyl group.

1.126 A compound according to Embodiment 1.125 wherein R⁶ is hydrogen.

1.127 A compound according to Embodiment 1.125 wherein R⁶ is a methylgroup.

1.128 A compound according to Embodiment 1.69 wherein Q¹ and Q² togetherwith X¹ and X² form a monocyclic group.

1.129 A compound according to Embodiment 1.128 wherein the monocyclicgroup is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group ora cyclohexyl group.

1.130 A compound according to Embodiment 1.129 wherein the monocyclicgroup is a cyclopropyl group.

1.131 A compound according to Embodiment 1.129 wherein the monocyclicgroup is a cyclobutyl group.

1.132 A compound according to Embodiment 1.129 wherein the monocyclicgroup is a cyclopentyl group.

1.133 A compound according to Embodiment 1.129 wherein the monocyclicgroup is a cyclohexyl group.

1.134 A compound according to any one of Embodiments 1.128 to 1.133wherein V is NH.

1.135 A compound according to any one of Embodiments 1.128 to 1.133wherein V is NHCH₂.

1.136 A compound according to any one of Embodiments 1.1 to 1.135wherein the moiety:

is selected from groups A to GG below:

where “a” indicates the point of attachment to the cyclohexane ring and“b” indicates the point of attachment to the W group.

1.137 A compound according to Embodiment 1.1 having the formula (2):

or a salt thereof, wherein the ring A is a phenyl or pyridyl ring; n is0, 1 or 2;

Q⁶ is halogen, methyl, cyano or methoxy;

R⁹ is selected from hydrogen, fluorine, hydroxy, methyl, ethyl andmethoxy;

R⁴ is hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one,two or three, but not all, carbon atoms of the hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof; and

R⁶ is hydrogen or C₁₋₄ alkyl.

1.138 A compound of the formula (3):

or a salt thereof, wherein:

Q⁴ is an optionally substituted five or six membered aromaticcarbocyclic or heterocyclic group containing 0, 1, 2 or 3 heteroatomring members selected from O, N and S;

Q⁵ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁹ is selected from hydrogen, fluorine, hydroxy, methyl, ethyl andmethoxy;

R⁴ is hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one,two or three, but not all, carbon atoms of the hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof; and

R⁶ is hydrogen or C₁₋₄ alkyl.

1.139 A compound according to formula (3) wherein Q⁴ and the pyrrolidinering are in a cis relative orientation.

1.140 A compound according to 1.138 or 1.139 wherein Q⁴ is an optionallysubstituted phenyl group or an optionally substituted pyridyl group.

1.141 A compound according to 1.140 wherein Q⁴ is an optionallysubstituted phenyl group or an optionally substituted 2-pyridyl group.

1.142 A compound according to 1.138 wherein either Q⁴ is unsubstitutedor is substituted with 1, 2 or 3 substituents Q⁶ selected from halogen;cyano; and R^(a)—R^(b); wherein:

R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, S, SO, SO₂ or NR^(c);

R^(b) is selected from hydrogen and a C₁₋₉ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S orby a group selected from CO, X¹C(X²), C(X²)X¹, SO and SO₂;

R^(c) is hydrogen or a 014 hydrocarbon group;

X¹ is 0, S or NR^(c); and

X² is ═O, ═S or ═NR^(c).

1.143 A compound according to 1.138 wherein Q⁴ is unsubstituted or issubstituted with 1 or 2 substituents Q⁶ selected from fluorine;chlorine; bromine; C₁₋₅ alkyl optionally substituted with one to threefluorine atoms; C₁₋₅ alkoxy optionally substituted with one to threefluorine atoms; and C₁₋₅ alkoxycarbonyl.

1.144 A compound according to 1.143 wherein Q⁴ is unsubstituted or issubstituted with a single substituent Q⁶ selected from fluorine;chlorine; methyl and methoxy.

1.145 A compound according to any one of 1.138 to 1.144 wherein Q⁵ isselected from cyano and C₁₋₂alkoxycarbonyl.

1.146 A compound according to any one of 1.138 to 1.145 wherein R⁹ isselected from hydrogen, hydroxy and fluorine.

1.147 A compound according to any one of 1.138 to 1.146 wherein R⁴ isselected from hydrogen; C₁₋₄ alkyl optionally substituted with one tothree fluorine atoms; C₁₋₂ alkoxy; C₁₋₃ alkyl and C₂₋₃ alkynyl.

1.148 A compound according to any one of 1.138 to 1.147 wherein R⁶ isselected from hydrogen and methyl.

1.149 A compound according to any previous embodiment, wherein thecompound is selected from

-   ethyl [(3S)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]carbamate-   ethyl [(3R)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]carbamate-   ethyl    {(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(2-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(2-methylphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(3-methylphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-(3-chlorophenyl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(3-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(5-fluoropyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-[4-cyano-4-(6-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3R)-1-[4-cyano-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate-   ethyl    {(3S)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl}methylcarbamate-   ethyl    {(3R)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl}methylcarbamate-   ethyl    {(3R)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}methylcarbamate.

1.150 A compound of the formula (4):

or a salt thereof, wherein:

Q⁴ is an optionally substituted five or six membered aromaticcarbocyclic or heterocyclic group containing 0, 1, 2 or 3 heteroatomring members selected from O, N and S;

Q⁵ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁹ is selected from hydrogen, fluorine, hydroxy and methoxy; and

R⁴ is hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one,two or three, but not all, carbon atoms of the hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S andoxidised forms thereof.

1.151 A compound according to formula 4 wherein Q⁴ is an optionallysubstituted five or six membered aromatic carbocyclic or heterocyclicgroup selected from optionally substituted phenyl; optionallysubstituted pyridyl; optionally substituted imidazolyl; and optionallysubstituted thienyl.

1.152 A compound according to 1.102 or 1.103 wherein either Q⁴ isunsubstituted or is substituted with 1, 2 or 3 substituents Q⁶ selectedfrom halogen; cyano; and R^(a)—R^(b); wherein:

R^(a) is a bond, O, CO, X¹C(X²), C(X²)X¹, S, SO, SO₂ or NR^(c);

R^(b) is selected from hydrogen and a C₁₋₉ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S orby a group selected from CO, X¹C(X²), C(X²)X¹, SO and SO₂;

R^(c) is hydrogen or a 014 hydrocarbon group;

X¹ is O, S or NR^(c); and

X² is ═O, ═S or ═NR^(c).

1.153 A compound according to 1.104 wherein Q⁴ is unsubstituted or issubstituted with 1 or 2 substituents Q⁶ selected from fluorine;chlorine; bromine; C₁₋₄ alkyl optionally substituted with one to threefluorine atoms; and C₁₋₄ alkoxy.

1.154 A compound according to 1.102 wherein Q⁴ is selected from:

phenyl which is unsubstituted or substituted with one or twosubstituents selected from fluorine; chlorine; bromine; C₁₋₄ alkyloptionally substituted with one to three fluorine atoms; and C₁₋₄alkoxy;

pyridyl which is unsubstituted or substituted with one or twosubstituents selected from fluorine; chlorine; bromine; C₁₋₄ alkyloptionally substituted with one to three fluorine atoms; C₁₋₄ alkoxy;and C₁₋₄alkoxycarbonyl;

thienyl; and

imidazolyl which is unsubstituted or substituted with one or two C₁₋₄alkyl substituents.

1.155 A compound according to any one of embodiments 1.150 to 1.154wherein Q⁵ is selected from hydrogen, cyano and C₁₋₂alkoxycarbonyl.

1.156 A compound according to any one of embodiments 1.150 to 1.155wherein R⁹ is selected from hydrogen, hydroxy and fluorine.

1.157 A compound according to any one of embodiments 1.149 to 1.155wherein R⁴ is selected from hydrogen, C₁₋₄ alkyl optionally substitutedwith one to three fluorine atoms and C₂₋₃ alkynyl.

1.158 A compound according to 1.157 wherein R⁴ is selected fromhydrogen, methyl, fluoromethyl, ethynyl and propynyl.

1.159 A compound according to any previous embodiment, wherein thecompound is selected from

-   ethyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(3-fluorophenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(2-chlorophenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(3-chlorophenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(4-chlorophenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(2-methylphenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(3-methylphenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(4-methoxyphenyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-{4-cyano-4-[2-(trifluoromethyl)phenyl]cyclohexyl}-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(pyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(pyridin-4-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(3-chloropyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(4-methylpyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-fluoropyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-bromopyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-methylpyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(5-ethoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-{4-cyano-4-[5-(trifluoromethyl)pyridin-2-yl]cyclohexyl}-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(6-methylpyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-{4-cyano-4-[6-(trifluoromethyl)pyridin-2-yl]cyclohexyl}-1,4-diazepane-1-carboxylate-   ethyl    4-[4-cyano-4-(thiophen-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-(4-cyano-4-phenylcyclohexyl)-6-fluoro-1,4-diazepane-1-carboxylate-   ethyl    4-(4-cyano-4-phenylcyclohexyl)-6-hydroxy-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]-6-fluoro-1,4-diazepane-1-carboxylate-   methyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate-   2-fluoroethyl    4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate-   but-2-yn-1-yl    4-[4-cyano-4-(pyridin-4-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   prop-2-yn-1-yl    4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   but-2-yn-1-yl    4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(methoxycarbonyl)-4-phenylcyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(3-chloropyridin-2-yl)-4-(methoxycarbonyl)cyclohexyl]-1,4-diazepane-1-carboxylate-   ethyl    4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate.

1.160 A compound according to any one of Embodiments 1.20 to 1.135wherein Z is C.

1.161 A compound according to any one of Embodiments 1.20 to 1.135wherein a single Z is N. 1.162 A compound according to Embodiment 1.112having the formula (5a), (5b), (5c) or (5d):

or a salt thereof, wherein:

p is 0, 1 or 2;

Q¹ and Q² are each nitrogen or carbon; provided that at least one of Q¹and Q² is nitrogen;

Q³ is a bond or a group -(Alk)_(q)-NR⁶ where Alk is an alkyl group of 1to 4 carbon atoms;

q is 0 or 1; and R⁶ is hydrogen or a saturated C₁₋₄ hydrocarbon group;provided that when Q² is nitrogen and Q³ is a group -(Alk)_(q)-NR⁶,there are at least two carbon atoms in line between Q² and NR⁶ andprovided that when Q³ is a bond, Q² is nitrogen;

X¹ and X² are optionally substituted saturated hydrocarbon groups whichtogether contain a total of three to nine carbon atoms and which linktogether such that the moiety:

forms a monocyclic or bicyclic ring system;

R¹ is H, OH, COOR⁷, CONR⁷R⁸, SO₂R⁷ or an optionally substituted C₁₋₆non-aromatic hydrocarbon group where one or more carbon atoms isoptionally replaced with a heteratom selected from O, N or S;

R² is selected from hydrogen; halogen; cyano; hydroxy; amino; and a C₁₋₄non-aromatic hydrocarbon group which is optionally substituted with oneto six fluorine atoms and wherein one or two, but not all, carbon atomsof the hydrocarbon group may optionally be replaced by a heteroatomselected from O, N and S and oxidized forms thereof;

R³ is selected from hydrogen or oxo;

Y is CH or O;

R⁴ is hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof;

R⁵ is fluorine or a C₁₋₄ hydrocarbon group; and

R⁷ and R⁸ are independently H or a C₁₋₄ hydrocarbon group.

1.163 A compound having formula (6)

or a salt thereof, wherein:

p is 0, 1 or 2;

V is selected from a bond, NH, N(C₁₋₃ alkyl), NH—CH₂ and N(C₁₋₃alkyl)-CH₂;

Q¹ is nitrogen or carbon; provided that at least one of Q¹ or Vcomprises a nitrogen atom;

X¹ and X² are optionally substituted saturated hydrocarbon groups whichtogether contain a total of one to nine carbon atoms and which linktogether such that the moiety:

forms a monocyclic or bicyclic ring system;

Q⁴ is an optionally substituted five or six membered aromaticcarbocyclic or heterocyclic group containing 0, 1, 2 or 3 heteroatomring members selected from O, N and S, or forms an optionallysubstituted heterocyclic spirocyclic ring with Q⁵;

Q⁵ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof, or formsan optionally substituted heterocyclic spirocyclic ring with Q⁴;

R¹⁰ is hydrogen or a C₁₋₄ hydrocarbon group which is optionallysubstituted with one to six fluorine atoms; and

R⁵ is fluorine or a C₁₋₄ hydrocarbon group.

1.164 A compound according to any previous embodiment, wherein thecompound is selected from

-   ethyl    [(3S)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3R)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(7′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(6′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(4′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(6′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    methyl[(3S)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    methyl[(3R)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    4-{(3S)-3-[(ethoxycarbonyl)amino]pyrrolidin-1-yl}-2′-oxospiro[cyclohexane-1,3′-indole]-1′(2′H)-carboxylate-   ethyl    {(3S)-1-[1′-(2-amino-2-oxoethyl)-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl]pyrrolidin-3-yl}carbamate-   ethyl    [(3S)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-chloro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    methyl[(3R)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    methyl[(3R)-1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate-   ethyl    [1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)piperidin-4-yl]carbamate-   ethyl    {[1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)piperidin-4-yl]methyl}carbamate-   methyl    4-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   4-(4-butanoyl-1,4-diazepan-1-yl)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   4-{4-[(2E)-but-2-enoyl]-1,4-diazepan-1-yl}spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   ethyl    4-(7′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(6′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(4′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(6′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(6′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(6′-cyano-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-cyano-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-chloro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-[1′-(methylsulfonyl)-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl]-1,4-diazepane-1-carboxylate-   ethyl    4-[1′-(methylsulfonyl)-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl]-1,4-diazepane-1-carboxylate-   ethyl    4-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate-   ethyl    6-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate-   ethyl    8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate-   ethyl    4-[2-(ethoxycarbonyl)-2,8-diazaspiro[4.5]dec-8-yl]-2′-oxospiro[cyclohexane-1,3′-indole]-1′(2′H)-carboxylate-   ethyl    8-(4-cyano-4-phenylcyclohexyl)-2,8-diazaspiro[4.5]decane-2-carboxylate-   ethyl    7-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-3-carboxylate-   ethyl    5-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate-   ethyl    1-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate-   ethyl    3-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate-   ethyl    (4aS,7aS)-1-(4-cyano-4-phenylcyclohexyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate-   4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile-   4-{[(1R,3S)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-phenylcyclohexanecarbonitrile-   1-phenyl-4-{6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]hept-2-yl}cyclohexanecarbonitrile-   4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-phenylcyclohexanecarbonitrile-   1-(2-fluorophenyl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile-   1-(5-fluoropyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile-   1-(5-methoxypyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile-   4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-(5-methylpyridin-2-yl)cyclohexanecarbonitrile-   4-[(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   5′-methoxy-4-[(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   5′-methyl-4-[(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   6′-methyl-4-[(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   4-({[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}amino)spiro[cyclo    hexane-1,3′-indol]-2′(1′H)-one-   4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)spiro    [cyclohexane-1,3′-indol]-2′(1′H)-one-   5′-methyl-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   6′-methyl-4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   4-[6-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]hept-2-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   5′-methyl-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   5′-methoxy-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   4-[2-(3-ethyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one-   4-({[2-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}amino)-1-phenylcyclohexanecarbonitrile-   1-(5-fluoropyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile-   1-(5-methylpyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile

1.165 A compound according to any one of Embodiments 1.1 to 1.164 havinga molecular weight of less than 550, for example less than 500, or lessthan 450.

1.166 A compound according to any one of Embodiments 1.1 to 1.165 whichis in the form of a salt.

1.167 A compound according to Embodiment 1.166 wherein the salt is anacid addition salt.

1.168 A compound according to Embodiment 1.166 or Embodiment 1.167wherein the salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformula (1), is used to describe any form of intervention where acompound is administered to a subject suffering from, or at risk ofsuffering from, or potentially at risk of suffering from the disease ordisorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the severityof the pain.

In formula (1), X¹ and X² are saturated hydrocarbon groups whichtogether contain a total of four to nine carbon atoms and which linktogether such that the moiety:

forms a monocyclic or bicyclic ring system. The term “bicyclic ringsystem as used herein in the context of X¹ and X² includes fusedbicyclic systems, bridged bicyclic systems and spirocyclic systemscontaining two linked rings.

Bicyclic ring systems may be characterized herein according to thenumber of atoms in each ring. For example, the term “4.5 spirocyclicring system” may be used to define a spirocyclic ring system in whichone ring contains 4 ring members and the other ring contains 5 ringmembers, e.g. a ring system such as:

Similarly the term “4.6 fused bicyclic group” may be used to define afused ring system in which one ring contains 4 ring members and theother ring contains 6 ring members, e.g. a ring system such as:

The term “non-aromatic hydrocarbon group” (as in “C₁₋₁₀ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” and “cycloalkenyl”are used in their conventional sense (e.g. as defined in the IUPAC GoldBook) unless indicated otherwise.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R groups above, where stated, one or two but notall, carbon atoms of the non-aromatic hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof. It will be appreciated that when a carbon atom is replaced by aheteroatom, the lower valencies of the heteroatoms compared to carbonmeans that fewer atoms will be bonded to the heteroatoms than would havebeen bonded to the carbon atom that has been replaced. Thus, forexample, replacement of a carbon atom (valency of four) in a CH₂ groupby oxygen (valency of two) will mean that the resulting molecule willcontain two less hydrogen atoms and replacement of a carbon atom(valency of four) in a CH₂ group by nitrogen (valency of three) willmean that the resulting molecule will contain one less hydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—CEN, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂—CH₂—CH₂-chain with C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—,replacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom in a—CH₂—CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic acid)—CH₂—CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formula (1) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulfonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (1) include the salt forms of the compounds asdefined in Embodiments 1.166 to 1.168.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.167) may be formed witha wide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.167 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (1).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.200), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.168.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.201) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.168which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.202), the inventionprovides compositions containing a compound according to Embodiment1.201 having one or more chiral centres, wherein at least 55% (e.g. atleast 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound ofEmbodiment 1.201 is present as a single optical isomer (e.g. enantiomeror diastereoisomer).

In one general embodiment (Embodiment 1.203), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.201 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.204 the compound is presentas a single enantiomer.

In another embodiment (Embodiment 1.205), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.206 A compound according to Embodiment 1.131 which is in the form of aracemic mixture of optical isomers.

1.207 A compound according to Embodiment 1.131 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.207 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.208), the compound of any one of Embodiments1.1 to 1.207 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment (Embodiment 1.209),however, the compound of any one of Embodiments 1.1 to 1.207 may containone or more radioisotopes. Compounds containing such radioisotopes maybe useful in a diagnostic context.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to1.209 may form solvates. Preferred solvates are solvates formed by theincorporation into the solid state structure (e.g. crystal structure) ofthe compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates canbe prepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TGE),differential scanning calorimetry (DSC) and X-ray crystallography. Thesolvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.301 and 1.302, the inventionprovides:

1.301 A compound according to any one of Embodiments 1.1 to 1.209 in theform of a solvate.

1.302 A compound according to Embodiment 1.301 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.303), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.209 in an anhydrous form (e.g. anhydrouscrystalline form).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.303 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.401 A compound according to any one of Embodiments 1.1 to 1.303 in acrystalline form.

1.402 A compound according to any one of Embodiments 1.1 to 1.303 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.403 A compound according to any one of Embodiments 1.1 to 1.303 whichis in an amorphous form.

Prodrugs

The compounds of the formula (1) or (1a) as defined in any one ofEmbodiments 1.1 to 1.168 may be presented in the form of a pro-drug. By“prodrugs” is meant for example any compound that is converted in vivointo a biologically active compound of the formula (1), as defined inany one of Embodiments 1.1 to 1.168.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LI DEPT, etc.).For example, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.500), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.168 wherein the compound contains a functional group which isconvertable under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.168 arecomplexes (e.g. inclusion complexes or clathrates with compounds such ascyclodextrins, or complexes with metals) of the compounds of Embodiments1.1 to 1.168.

Accordingly, in another embodiment (Embodiment 1.600), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.168 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M₁receptor agonists. The muscarinic activity of the compounds can bedetermined using the Phospho-ERK1/2 assay described in Example A below.

A significant advantage of compounds of the invention is that they arehighly selective for the M₁ receptor relative to the M₂ and M₃ receptorsubtypes. Compounds of the invention are neither agonists of the M₂ andM₃ receptor subtypes. For example, whereas compounds of the inventiontypically have pEC₅₀ values of at least 6 (preferably at least 6.5) andE_(max) values of greater than 80 (preferably greater than 100) againstthe M₁ receptor in the functional assay described in Example A, they mayhave pEC₅₀ values of less than 5 and E_(max) values of less than 20%when tested against the M₂ and M₃ subtypes in the functional assay ofExample A.

Some compounds of the invention are also highly selective for the M₁receptor relative to the M₄ receptor. Examples of such compounds include1-1, 1-3, 1-4, 1-9, 1-10, 2-1, 2-3, 2-4, 2-5, 2-7, 2-8, 2-10, 2-17,3-19, 3-20, 3-31, 3-32, 4-7, 4-12 and 5-1.

Other compounds of the invention have activity at both the M₁ and M₄receptors. Examples of such compounds include 3-2, 3-3, 3-6, 3-8, 3-16,3-17, 4-6, 6-2, 12-1, 12-2 and 13-1.

Accordingly, in Embodiments 2.1 to 2.17, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.600 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.600 for useas a muscarinic M₁ receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.600 which isa muscarinic M₁ receptor agonist having a pEC₅₀ in the range from 6.0 to10.0 and an E_(max) of at least 90 against the M₁ receptor in the assayof Example A herein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ in the range from 6.5 to 10.0.

2.5 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ in the range from 6.8 to 7.9.

2.6 A compound according to Embodiment 2.3 which is a muscarinic M₁receptor agonist having a pEC₅₀ in the range from 7.1 to 7.9.

2.7 A compound according to Embodiments 2.3 to 2.6 having an E_(max) ofat least 95 against the M₁ receptor.

2.8 A compound according to any one of Embodiments 1.1 to 1.600 which isa muscarinic M₄ receptor agonist having a pEC₅₀ in the range from 6.0 to9.0 and an E_(max) of at least 90 against the M₄ receptor in the assayof Example A herein or an assay substantially similar thereto.

2.9 A compound according to Embodiment 2.8 which is a muscarinic M₄receptor agonist having a pEC₅₀ in the range from 6.5 to 9.0.

2.10 A compound according to Embodiment 2.8 or Embodiment 2.9 having anE_(max) of at least 95 against the M₄ receptor.

2.11 A compound according to any one of Embodiments 2.3 to 2.7 which isselective for the M₁ receptor compared to the muscarinic M₂ and M₃receptors.

2.12 A compound according to any one of Embodiments 2.3 to 2.11 whichhas a pEC₅₀ of less than 5 and an E_(max) of less than 50 against themuscarinic M₂ and M₃ receptor subtypes.

2.13 A compound according to Embodiment 2.12 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M₂ andM₃ receptor subtypes.

2.14 A compound according to any one of Embodiments 1.1 to 1.600 andEmbodiments 2.3 to 2.13 for use in the treatment of a disease orcondition mediated by the muscarinic M₁ receptor.

2.15 A compound according to any one of Embodiments 1.1 to 1.600 whichis selective for the M₁ receptor compared to the muscarinic M₂, M₃ andM₄ receptors.

2.16 A compound according to Embodiment 2.15 which has a pEC₅₀ of lessthan 5 and an E_(max) of less than 50 against each of the muscarinic M₂,M₃ and M₄ receptor subtypes.

2.17 A compound according to Embodiment 2.16 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the each of themuscarinic M₂, M₃ and M₄ receptor subtypes.

2.18 A compound according to any one of Embodiments 1.1 to 1.600 whichis selective for the M₁ and M₄ receptors compared to the muscarinic M₂and M₃ receptors.

2.19 A compound according to Embodiment 2.18 which has a pEC₅₀ of lessthan 5 and an E_(max) of less than 50 against each of the muscarinic M₂and M₃ receptor subtypes.

2.20 A compound according to Embodiment 2.19 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the each of themuscarinic M₂ and M₃ receptor subtypes.

By virtue of their muscarinic M₁ and/or M₄ receptor agonist activity,compounds of the invention can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M₁ and/or M₄receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.21 to 2.42, the invention provides:

2.21 A compound according to any one of Embodiments 1.1 to 1.600 for usein the treatment of a cognitive disorder or psychotic disorder.

2.22 A compound for use in according to Embodiment 2.21 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as Multiinfarctdementia, alcoholic dementia, hypotiroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders,epilepsy and schizo-affective disorder.

2.23 A compound according to any one of Embodiments 1.1 to 1.600 for usein the treatment of Alzheimer's disease.

2.24 A compound according to any one of Embodiments 1.1 to 1.600 for usein the treatment of Schizophrenia.

2.25 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.600.

2.26 A method according to Embodiment 2.25 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.22.

2.27 A method according to Embodiment 2.26 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.28 A method according to Embodiment 2.27 wherein the cognitivedisorder is Schizophrenia.

2.29 The use of a compound according to any one of Embodiments 1.1 to1.600 for the manufacture of a medicament for the treatment of acognitive disorder.

2.30 The use according to Embodiment 2.29 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.22.

2.31 The use according to Embodiment 2.30 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.32 The use according to Embodiment 2.30 wherein the cognitive disorderis Schizophrenia.

2.33 A compound according to any one of Embodiments 1.1 to 1.600 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.34 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.600.

2.35 A compound according to any one of Embodiments 1.1 to 1.600 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.36 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth including Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.600.

2.37 The use of a compound according to any one of Embodiments 1.1 to1.600 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.38 The use of a compound according to any one of Embodiments 1.1 to1.600 for the use in the treatment of skin lesions for example due topemphigus vulgaris, dermatitis herpetiformis, pemphigoid and otherblistering skin conditions.

2.39 The use of a compound according to any one of Embodiments 1.1 to1.600 for the use in treating, preventing, ameliorating or reversingconditions associated with altered gastro-intestinal function andmotility such as functional dyspepsia, irritable bowel syndrome,gastroesophageal acid reflux (GER) and esophageal dysmotility, symptomsof gastroparesis and chronic diarrhea.

2.40 The use of a compound according to any one of Embodiments 1.1 to1.600 for the use in in the treatment of olfactory dysfunction such asBosma-Henkin-Christiansen syndrome, chemical poisoning (e.g. seleniumand silver), hypopituitarism, Kallmann Syndrome, skull fractures, tumourtherapy and underactive thyroid gland.

2.41 The use of a compound according to any one of Embodiments 1.1 to1.600 for the treatment of addiction.

2.42 The use of a compound according to any one of Embodiments 1.1 to1.600 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon's disease, tourette's syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.168, which process comprises:

(A) when it is required to prepare a compound of formula (1) wherein Q¹is nitrogen, the reaction of a compound of the formula (10):

with a compound of the formula (11):

under reductive amination conditions; wherein p, Q¹, Q², Q⁴, Q⁵, R⁵, V,W, X¹ and X² are as defined in any one of Embodiments 1.1 to 1.168; or

(B) when it is required to prepare a compound of formula (1) wherein Q²is nitrogen, W is -Q³C(O)YCH₂R⁴ and Q³ is a bond, the reaction of acompound of the formula (12):

with a compound of the formula Cl—C(═O)—O—CH₂—R⁴; wherein p, Q¹, Q⁴, Q⁵,R⁴, R⁵, V, X¹ and X² are as defined in any one of Embodiments 1.1 to1.168; or

(C) when it is required to prepare a compound of formula (1) wherein Q²is nitrogen, W is -Q³C(O)YCH₂R⁴ and Q³ is a group -(Alk)_(q)-NR⁶, thereaction of a compound of a compound of the formula (13):

with a compound of the formula Cl—C(═O)—O—CH₂—R⁴; wherein p, Q¹, Q², Q⁴,Q⁵, R⁴, R⁵, R⁶, V, X¹ and X² are as defined in any one of Embodiments1.1 to 1.168;

and optionally:

(D) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the mono-protected diamine (11) is reacted withthe substituted cyclohexanone (10) under reductive amination conditions.The reductive amination reaction is typically carried out at ambienttemperature to mild heating (e.g. to a temperature of about 20° C. toabout 70° C.) using either a borohydride reducing agent such as sodiumtriacetoxy-borohydride in a solvent such as dichloromethane ordichloroethane containing acetic acid, or sodium cyanoborohydride incombination with zinc chloride, or sodium triacetoxy-borohydride incombination with titanium isopropoxide.

Substituted cyclohexanones of the formula (10) can be prepared by thesequence of reactions shown in Scheme 1 below. Thus, a protectedsubstituted cyclohexanone (14) is deprotonated using a suitable basesuch as lithium diisopropylamide (LDA), sodium hexamethyldisilazide(NaHMDS) or potassium hexamethyldisilazide (KHMDS) and then reacting theanion with a suitable reactive organohalide (15) to give the protectedsubstituted cyclohexanones (16). This is then deprotected by removal ofthe cyclic acetal group using an organic acid such as trifluoroaceticacid in dichloromethane or an inorganic acid such as HCl in dioxane togive the substituted cyclohexanones (10), as shown in Scheme 1.

An alternate route to substituted cyclohexanones of the formula (10) isshown in Scheme 2. Alkyl compounds of the formula (17) can deprotonatedusing a suitable base such as tBuOK, NaHMDS or KHMDS and then reactingthe anion with methyl acrylate to give the protected substitutedcyclohexanone (18). These can be decarboxylated by treating with asuitable base such as tBuOK, LiOH or NaOH followed by heating to givethe substituted cyclohexanones (10).

Once formed, one compound of the formula (1), or a protected derivativethereof, can be converted into another compound of the formula (1) bymethods well known to the skilled person. Examples of syntheticprocedures for converting one functional group into another functionalgroup are set out in standard texts such as Advanced Organic Chemistryand Organic Syntheses (see references above) or Fiesers' Reagents forOrganic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser(ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Once formed, one compound of the formula (1), or a protected derivativethereof, can be converted into another compound of the formula (1) bymethods well known to the skilled person. Examples of syntheticprocedures for converting one functional group into another functionalgroup are set out in standard texts such as Advanced Organic Chemistryand Organic Syntheses (see references above) or Fiesers' Reagents forOrganic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser(ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Methods for the Preparation of Compounds of the Formula (1a)

Compounds of the formula (1a) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.2), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.20 to 1.168, which process comprises:

(A) when it is required to prepare a compound of formula (1a) wherein Q¹is nitrogen, the reaction of a compound of the formula (10a):

with a compound of the formula (11a):

under reductive amination conditions; wherein p, Z, Q¹, Q², Q³, R¹, R²,R³, R⁵, V, W, X¹ and X² are as defined in any one of Embodiments 1.20 to1.168; or

(B) when it is required to prepare a compound of formula (1a) wherein Q²is nitrogen, W is -Q³C(O)YCH₂R⁴ and Q³ is a bond, the reaction of acompound of the formula (12a):

with a compound of the formula Cl—C(═O)—O—CH₂—R⁴; wherein p, Z, Q¹, R¹,R², R³, R⁴, R⁵, V, X¹ and X² are as defined in any one of Embodiments1.20 to 1.168; or

(C) when it is required to prepare a compound of formula (1a) wherein Q²is nitrogen, W is -Q³C(O)YCH₂R⁴ and Q³ is a group -(Alk)_(q)-NR⁶, thereaction of a compound of a compound of the formula (13a):

with a compound of the formula Cl—C(═O)—O—CH₂—R⁴; wherein p, q, Z, Q¹,Q², R¹, R², R³, R⁴, R⁵, R⁶, V, X¹ and X² are as defined in any one ofEmbodiments 1.1 to 1.168;

and optionally:

(D) converting one compound of the formula (1a) to another compound ofthe formula (1a).

In process variant (A), the mono-protected diamine (11a) is reacted withthe substituted cyclohexanone (10a) under reductive aminationconditions. The reductive amination reaction is typically carried out atambient temperature to mild heating (e.g. to a temperature of about 20°C. to about 70° C.) using either a borohydride reducing agent such assodium triacetoxy-borohydride in a solvent such as dichloromethane ordichloroethane containing acetic acid, or sodium cyanoborohydride incombination with zinc chloride, or sodium triacetoxy-borohydride incombination with titanium isopropoxide.

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Once formed, one compound of the formula (1a), or a protected derivativethereof, can be converted into another compound of the formula (1a) bymethods well known to the skilled person. Examples of syntheticprocedures for converting one functional group into another functionalgroup are set out in standard texts such as Advanced Organic Chemistryand Organic Syntheses (see references above) or Fiesers' Reagents forOrganic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser(ISBN: 0-471-58283-2).

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) as defined in any one of Embodiments 1.1 to1.600 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 miligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 25-1

The compounds of Examples 1-1 to 25-1 shown in Table 1 below have beenprepared. Starting materials and intermediates are described in Table 2.The NMR and LCMS properties of the compounds of Examples 1-1 to 25-1 andthe methods used to prepare them are set out in Table 3.

TABLE 1

Example 1-1

Example 1-2

Example 1-3

Example 1-4

Example 1-5

Example 1-6

Example 1-7

Example 1-8

Example 1-9

Example 1-10

Example 1-11

Example 1-12

Example 1-13

Example 1-14

Example 1-15

Example 1-16

Example 1-17

Example 1-18

Example 1-19

Example 1-20

Example 1-21

Example 1-22

Example 2-1

Example 2-2

Example 2-3

Example 2-4

Example 2-5

Example 2-6

Example 2-7

Example 2-8

Example 2-9

Example 2-10

Example 2-11

Example 2-12

Example 2-13

Example 2-14

Example 2-15

Example 2-16

Example 2-17

Example 2-18

Example 2-19

Example 2-20

Example 2-21

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 3-5

Example 3-6

Example 3-7

Example 3-8

Example 3-9

Example 3-10

Example 3-11

Example 3-12

Example 3-13

Example 3-14

Example 3-15

Example 3-16

Example 3-17

Example 3-18

Example 3-19

Example 3-20

Example 3-21

Example 3-22

Example 3-23

Example 3-24

Example 3-25

Example 3-26

Example 3-27

Example 3-28

Example 3-29

Example 3-30

Example 3-31

Example 3-32

Example 3-33

Example 3-34

Example 4-1

Example 4-2

Example 4-3

Example 4-4

Example 4-5

Example 4-6

Example 4-7

Example 4-8

Example 4-9

Example 4-10

Example 4-11

Example 4-12

Example 4-13

Example 4-14

Example 4-15

Example 4-16

Example 4-17

Example 4-18

Example 4-19

Example 4-20

Example 4-21

Example 4-22

Example 4-23

Example 4-24

Example 5-1

Example 6-1

Example 6-2

Example 7-1

Example 7-2

Example 8-1

Example 9-1

Example 10-1

Example 11-1

Example 12-1

Example 12-2

Example 13-1

Example 14-1

Example 15-1

Example 16-1

Example 17-1

Example 18-1

Example 19-1

Example 19-2

Example 20-1

Example 21-1

Example 21-2

Example 21-3

Example 21-4

Example 21-5

Example 22-1

Example 22-2

Example 22-3

Example 22-4

Example 23-1

Example 24-1

Example 24-2

Example 24-3

Example 25-1

Example 26-1

Example 26-2

Example 26-3

Example 27-1

Example 28-1

Example 28-2

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (□)-values. The following abbreviations are used forthe multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. TLCfor monitoring reactions refers to TLC run using the specified mobilephase and the Silica gel F254 as a stationary phase from Merck.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

Mass spectroscopy was carried out on Shimadzu LC-2010 EV, WatersZQ-2000, UPLC-Mass SQD-3100 or Applied Biosystem API-2000 spectrometersusing electrospray conditions as specified for each compound in thedetailed experimental section.

Preparative HPLC was typically carried out under the followingconditions, (Waters HPLC): Column: XSelect CSH Prep C-18, 19×50 mm, 5μm; Mobile phase: Gradients of water and MeCN (each containing 0.1%Formic Acid); gradient 5% MeCN in 0.1 HCOOH in water (30 sec), 5% to 40%(over 7 min) then 95% MeCN in 0.1 HCOOH in water (1 min) then 5% MeCN in0.1 HCOOH in water (1.5 min) at 28 mL/min. Additionally, preparativeHPLC was also carried out using Method A below:

Preparative HPLC Method A

Instruments: Gilson Semi Preparative HPLC system including a 321 Pump,GX-271 Liquid Handler with Gilson Trilution software and Gilson 171 DADwith collection at 205 nm unless otherwise stated; Column: PhenomenexGemini-NX C-18, 5 micron, 30×100 mm; Flow rate: 30 mL/min; Solvents:solvent C=2.5 L of water and 5 mL of 28% ammonia in water solution,solvent D=2.5 L of acetonitrile; Gradient: all narrow gradients followthe same profile exemplified for 5-95% below, written in the format,[Time (min)/% C:% D], 12.5 min 5-95% gradient: [0.00/95:5], [0.3/95:5],[9.0/5:95], [9.5/5:95], [9.7/0:100], [10.7/0:100], [10.9/95:5],[11.5/95:5]

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions:

Method A

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C(%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2;Solvents: solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 LMeCN+135 mL H₂O+2.5 mL ammonia solution); Injection volume 3 uL; UVdetection 230 to 400 nM; column temperature 45° C.; Flow rate 1.5mL/min.

Method B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent Din C(%)]: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents:solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

Method C

Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent6120B Single Quadrupole MS with API-ES Source; Column: PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A(%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents:solvent A=2.5 L H₂O+2.5 mL of (28% NH₃ in H₂O); solvent B=2.5 L MeCN+129mL H₂O+2.7 mL of (28% NH₃ in H₂O); Injection volume 0.5 μL; UV detection190 to 400 nM; column temperature 40° C.; Flow rate 1.5 mL/min.

Method D

Instrument: Waters Acquity H-class UPLC with SQ detector using BEH C18(50*2.1 mm id 1.7 μm) and using water (0.1% Ammonium Hydroxide) and MeCN(0.1% Ammonium Hydroxide) as the mobile phase. The eluent gradientprogram was MeCN (0.1% Ammonium Hydroxide) from 10% to 100% for 2.5 min,100% MeCN (0.1% Ammonium Hydroxide) for 2 min and MeCN (0.1% AmmoniumHydroxide) from 100% to 10% for 0.5 min. The flow rate was 0.3 mL/min.

Method E

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: WatersX-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: 0.00/2,0.10/2, 8.40/95, 10.00/95; Solvents: solvent C=2.5 L H₂O+2.5 mL 28%ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mL H₂O+2.5 mL 28%ammonia in H₂O solution); Injection volume 1 μL; UV detection 230 to 400nM; Mass detection 130 to 800 AMU (+ve and −ve electrospray); columntemperature 45° C.; Flow rate 1.5 mL/min.

Method F

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5;Solvents: solvent A=5 mM Ammonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic acid in MeCN; Injection volume 2 μL; UV detection200 to 400 nM; Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

Method G

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

Method H

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

Method I

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 150×4.6 mm; Gradient [time (min)/solvent B inA (%)]: 0.00/5, 5.00/90, 5.80/95, 10/95; Solvents: solvent A=0.1%ammonia in H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 □L;UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+veelectrospray); column at ambient temperature; Flow rate 1.0 mL/min.

Method K

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

Method L

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity BEH C-18, 1.7 micron, 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/2, 2.00/2, 7.00/50, 8.50/80, 9.50/2, 10.0/2; Solvents:solvent A=5 mM ammonium acetate in water; solvent B=acetonitrile;Injection volume 1 μL; Detection wavelength 214 nm; Column temperature30° C.; Flow rate 0.3 mL per min.

Method O

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity HSS-T3, 1.8 micron, 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90,9.00/10, 10.00/10; Solvents: solvent A=0.1% trifluoroacetic acid inwater; solvent B=acetonitrile; Injection volume 1 μL; Detectionwavelength 214 nm; Column temperature 30° C.; Flow rate 0.3 mL per min.

Method P

Instruments: Waters Acquity H Class, Waters 3100 PDA Detector, SQD;Column: BEH C18 2.1×50 mm, 1.7 micron; Gradient [time (min)/solvent B inA (%)]: 0.00/5, 0.40/5, 2.50/95, 3.50/95, 3.51/5, 4.00/5; Solvents:solvent A=5 mM ammonium acetate and 0.1% formic acid in water; solventB=0.1% formic acid in acetonitrile.

Method Q

Instruments: Waters Acquity H Class, Waters 3100 PDA Detector, SQD;Column: BEH C18 2.1×50 mm, 1.7 micron; Gradient [time (min)/solvent B inA (%)]: 0.00/5, 0.40/5, 0.80/35, 1.20/55, 2.70/95, 3.30/95, 3.31/5,4.00/5; Solvents: solvent A=5 mM ammonium acetate and 0.1% formic acidin water; solvent B=0.1% formic acid in acetonitrile.

Method R

Instruments: Shimadzu Nexera, Photo Diode Array, LCMS-2020 Detector,Column: X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time(min)/solvent B in A (%)]: 0.01/5, 5.00/90, 5.80/95, 7.20/95, 7.21/100,10.00/100; Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1%ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM;Mass detection 60 to 1000 AMU (+ve electrospray); column at ambienttemperature; Flow rate 1.0 mL/min.

Method S

Instruments: Agilent 1290 RRLC with Agilent 6120 Mass detector, PhotoDiode Array, Agilent 6120 Detector, Column: X-Bridge C18, 3.5 micron,50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.01/5, 5.00/90,5.80/95, 7.20/95, 7.21/100, 10.00/100; Solvents: solvent A=0.1% ammoniain H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UVdetection 200 to 400 nM; Mass detection 60 to 1000 AMU (+veelectrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, UV activity.

ABBREVIATIONS

-   AcOH=acetic acid-   aq.=aqueous-   d=day(s)-   DCM=dichloromethane-   DIPEA=diisopropylethylamine-   DMF=dimethylformamide-   DMSO=dimethylsulfoxide-   ES=electro spray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HCl=hydrogen chloride, hydrochloric acid-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   MeCN=acetonitrile-   MeOH=Methanol-   min, mins=minute(s)-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   rt, RT=room temperature-   sat.=saturated-   sol.=solution-   STAB=sodium triacetoxyborohydride-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Prefixes n-, s-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

Synthesis of Intermediates

Route 1

Typical procedure for the preparation of amines, as exemplified by thepreparation of Intermediate 6, trifluoroacid salt of ethyl2,8-diazaspiro[4.5]decane-2-carboxylate

tert-Butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (481 mg, 2.0 mmol)was dissolved in DCM (20.0 mL) and triethylamine (0.61 g, 0.84 mL, 6.0mmol) was added. The reaction mixture was cooled to 0° C., ethylchloroformate (0.33 g, 0.29 mL, 3.0 mmol) was added and the reactionmixture was stirred at rt overnight. The reaction mixture waspartitioned between water (20 mL) and DCM (20 mL), the aqueous layer wasfurther extracted with DCM (3×20 mL), the organic layers were combinedand dried (Na₂SO₄). The solvent was removed in vacuo to give crude8-tert-butyl 2-ethyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate as acolourless gum which was used directly without further purification.

LCMS (Method C): m/z 313 (M+H)⁺ (ES⁺), at 1.45 min, UV inactive.

8-tert-Butyl 2-ethyl 2,8-diazaspiro[4.5]decane-2,8-dicarboxylate(assumed 2.0 mmol) was dissolved in DCM (5 mL), cooled to 0° C.,trifluoroacetic acid (5 mL) was added and the reaction mixture wasstirred at rt overnight. The solvents were removed in vacuo, the residuewas dissolved in toluene (20 mL), and then concentrated in vacuo (threetimes), to give ethyl 2,8-diazaspiro[4.5]decane-2-carboxylatetrifluoroacetate salt (0.65 g, 99%) as a colourless gum which was useddirectly without further purification.

The data for Intermediate 6 are in Table 2

Route 2

Typical procedure for the preparation of amines, as exemplified by thepreparation of Intermediate 13, ethyl (3S)-pyrrolidin-3-ylcarbamatehydrochloride

tert-Butyl (3S)-3-aminopyrrolidine-1-carboxylate (1.00 g, 5.37 mmol) wasdissolved in DCM (25.0 mL) and NEt₃ (1.63 g, 16.12 mmol) was added. Theresulting reaction mixture was cooled to 0° C. and ethyl chloroformate(0.70 g, 6.45 mmol) was added. The reaction mixture was stirred for 30min at rt, then partitioned between water (25 mL) and EtOAc (30 mL), theaqueous layer was further extracted with EtOAc (2×30 mL), and theorganic layers were combined and dried (Na₂SO₄). The solvent was removedin vacuo to give tert-butyl(3S)-3-[(ethoxycarbonyl)amino]pyrrolidine-1-carboxylate (1.3 g, 94.2%)as a colourless gum.

Mass: (ESI +ve): 259 (M+H)⁺.

tert-Butyl (3S)-3-[(ethoxycarbonyl)amino]pyrrolidine-1-carboxylate (1.3g, 5.03 mmol) was dissolved in 1, 4-Dioxane (10 mL) and HCl in1,4-Dioxane (20.0 mL, 1.0M) was added. The reaction mixture was stirredat rt for 16 h. The solvent was removed in vacuo, and the residue waspurified by trituration with acetone (2×10 mL) to give ethyl(3S)-pyrrolidin-3-ylcarbamate hydrochloride (0.5 g, 62.8%) as a whitesolid.

The data for Intermediate 13 are in Table 2

Route 3 Typical procedure for the preparation of cyclohexanonescontaining substituted aryl groups, as exemplified by the preparation ofIntermediate 20, 1-(3-fluorophenyl)-4-oxocyclohexanecarbonitrile

2-(3-Fluorophenyl) acetonitrile (2.0 g, 14.8 mmol) and methyl acrylate(2.67 g, 31.07 mmol) were dissolved in THF (70 mL). The reaction mixturewas cooled to 0° C. and t-BuOK (1.0 M in THF, 17.73 mL, 17.75 mmol) wasadded. The reaction mixture was stirred at rt for 1 h and then quenchedwith ice cold water, and the pH adjusted to pH=4 with aqueous 8% citricacid (54 mL). The reaction mixture was extracted with EtOAc (4×75 mL),the organic layers were combined and dried (Na₂SO₄). The solvent wasremoved in vacuo, and the residue was purified by column chromatography(normal phase, silica, 60-120 mesh, gradient 0% to 5% EtOAc in hexane)to give methyl 5-cyano-5-(3-fluorophenyl)-2-oxocyclohexanecarboxylate(3.2 g, 78.8%) as an off white solid.

Mass: (ESI +ve): 276 (M+H)⁺.

Methyl 5-cyano-5-(3-fluorophenyl)-2-oxocyclohexanecarboxylate (1.05 g,3.81 mmol) was dissolved in THF/Water (2:1) (36 mL) and t-BuOK (514 mg,4.58 mmol) was added at rt. The reaction mixture was heated at 105° C.for 5 h, then cooled to rt and partitioned between EtOAc (100 mL) andwater (50 mL). The aqueous layer was extracted with EtOAc (2×100 mL) andthe organic layers were combined and dried (Na₂SO₄). The solvent wasremoved in vacuo and the residue was purified by column chromatography(normal phase silica, 0 to 11% EtOAc in hexane) to give1-(3-fluorophenyl)-4-oxocyclohexanecarbonitrile (0.51 g, 64.6%) as anoff white solid.

The data for Intermediate 20 are in Table 2

Route 4

Typical procedure for the preparation of cyclohexanones containingsubstituted pyridyl groups, as exemplified by the preparation ofIntermediate 27, 1-(5-fluoropyridin-2-yl)-4-oxocyclohexanecarbonitrile

1,4-Dioxaspiro-(4,5)-decane-8-carbonitrile (2.0 g, 11.9 mmol) wasdissolved in PhMe (20.0 mL) and 2-bromo-5-fluoropyridine (2.0 g, 11.9mmol) was added. The reaction mixture was cooled to −78° C. and NaHMDS(5.47 g, 29.9 mL 1.0M in THF, 29.9 mmol) was added. The reaction mixturewas stirred for 30 minutes at −78° C. and warmed to rt overnight, thenquenched with water (100 mL). The reaction mixture was partitionedbetween PhMe (100 mL) and water (50 mL), the aqueous layer was extractedwith PhMe (2×100 mL) and the organic layers were combined and dried(Na₂SO₄). The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, silica, 60-120 mesh,gradient 0% to 12% EtOAc in Hexane) to give8-(5-fluoropyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.2g, 40%).

8-(5-Fluoropyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.0g, 3.81 mmol) was dissolved in DCM (5.0 mL) and TFA (3.0 mL) was added.The reaction mixture was stirred at rt for 5h. The reaction mixture waspartitioned between DCM (100 mL) and water (50 mL), the aqueous layerwas extracted with DCM (2×100 mL) and the organic layers were combinedwashed with brine (25 mL) and dried (Na₂SO₄). The solvents were removedin vacuo, and the residue was purified by column chromatography (normalphase, silica, 60-120 mesh, gradient 0% to 10% EtOAc in hexane) to give1-(5-fluoropyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.8 g, 96%).

The data for Intermediate 27 are in Table 2

For less reactive substrates, heating conditions may be required forstep 1.

Route 5

Typical procedure for the preparation of cyclohexanone carboxylatescontaining substituted pyridyl groups, as exemplified by the preparationof Intermediate 50, methyl1-(3-chloropyridin-2-yl)-4-oxocyclohexanecarboxylate

1-(3-Chloropyridin-2-yl)-4-oxocyclohexanecarbonitrile (4.0 g, 17.1 mmol)was dissolved in MeOH (40 mL) and H₂SO₄ (20 mL) was added. The reactionmixture was heated at 100° C. for 16 h, cooled to rt and DCM (100 mL)and water (50 mL) were added. The pH was adjusted to pH 8 with theaddition of solid NaHCO₃. The aqueous layer was extracted with DCM (2×50mL) and the organic layers were combined washed with brine (25 mL) anddried (Na₂SO₄). The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, silica, 60-120 mesh,gradient 0% to 20% EtOAc in hexane) to give methyl1-(3-chloropyridin-2-yl)-4-oxocyclohexanecarboxylate (0.4 g, 8.8%).

The data for Intermediate 50 are in Table 2

Route 6

Typical procedure for the preparation of spiroketones from thecorresponding oxindole, exemplified by the preparation of Intermediate67, 7′-methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione

7-methyl-1,3-dihydro-2H-indol-2-one (2.00 g, 13.5 mmol) and anhydrouspotassium tert-butoxide (0.08 g, 0.7 mmol) were dissolved in DMSO (10mL) under N₂. Methyl acrylate (3.50 g, 40.7 mmol) was added dropwiseover 30 min and the reaction mixture stirred at 45° C. for 15 min.Anhydrous potassium tert-butoxide (3.05 g, 27.2 mmol) was addedportionwise over 40 min and the reaction mixture allowed to stir at 60°C. for 2 h. Water (20 mL) was added to the reaction mixture with furtherstirring at 80° C. for 8 h. The mixture was diluted with water (250 mL),extracted with EtOAc (3×100 mL), combined organics dried (Na₂SO₄) andthe solvent removed in vacuo. The crude product was purified by columnchromatography (normal phase, neutral silica gel, 60-120 mesh, 0 to 30%EtOAc in hexane) to give7′-methylspiro[cyclohexane-1,3′-indoline]-2′,4-dione (230 mg, 7%) as abrown solid.

The data for Intermediate 67 are in Table 2

Route 7

Procedure for the preparation of pyrrolidines, exemplified by thepreparation of

Intermediate 84, ethyl methyl[(3R)-pyrrolidin-3-yl]carbamatetrifluoroacetic acid salt

To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g,8.0 mmol), Et₃N (3.4 mL, 24.1 mmol) in DCM (20 mL) was added ethylchloroformate (1.1 mL, 12.0 mmol) at 0° C. The reaction mixture wasstirred at rt for 1 h, partitioned between cold H₂O (25 mL) and DCM (50mL) and the aqueous layer further extracted with DCM (2×50 mL). Combinedorganics were dried (Na₂SO₄) and the solvent removed in vacuo. The crudeproduct was purified by column chromatography (normal-phase silica, 0 to6% MeOH in DCM) to give (R)-tert-butyl 3-(ethoxycarbonylamino)pyrrolidine-1-carboxylate (1.0 g, 49%) as a reddish gum.

LCMS (Method F): m/z 259 (M+H)⁺ (ES⁺), at 2.05 min, UV active.

To a solution of (R)-tert-butyl 3-(ethoxycarbonylamino)pyrrolidine-1-carboxylate (500 mg, 1.9 mmol) and NaH (60% w/w in mineraloil, 92 mg, 2.3 mmol) in DMF (10 mL) was added methyl iodide (230 μL,3.7 mmol) at rt and the reaction stirred for 1 h. The mixture waspartitioned between cold H₂O (100 mL) and EtOAc (100 mL) and the aqueouslayer further extracted with EtOAc (2×100 mL). Combined organics weredried (Na₂SO₄) and the solvent removed in vacuo to give tert-butyl(R)-3-((ethoxycarbonyl)(methyl)amino)pyrrolidine-1-carboxylate (500 mg,97%) as a reddish gum.

LCMS (Method F): m/z 217 [M+H−56]⁺ (ES⁺), at 2.23 min, UV active.

To a solution of (R)-tert-butyl 3-(ethoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (650 mg, 2.3 mmol) in DCM (20mL) was added TFA (540 μL, 7.1 mmol) at 0° C. and the reaction mixturestirred at rt for 16 h. The mixture was concentrated in vacuo to give(R)-ethyl methyl (pyrrolidin-3-yl) carbamate (400 mg, 61%) as a reddishgum.

The data for Intermediate 84 are in Table 2

Route 8

Typical procedure for the preparation of N-alkylated oxindoles,exemplified by the preparation of Intermediate 86,1′-methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione

To 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (395 mg, 1.8 mmol)and K₂CO₃ (507 mg, 3.7 mmol) in DMF (5 mL) at rt was added methyl iodide(286 mg, 2.0 mmol) dropwise and the reaction mixture heated to 100° C.for 16 h. The mixture was poured into ice cold water (100 mL), extractedwith EtOAc (50 mL) and the aqueous layer further extracted with EtOAc(2×50 mL). Combined organics were dried (Na₂SO₄) and the solvent removedin vacuo. The crude product was purified using column chromatography(normal phase silica, 0 to 10% EtOAc in hexane) to yield1′-Methyl-4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (250 mg,57%) as an off-white solid.

The data for Intermediate 86 are in Table 2

Route 9

Typical procedure for the preparation of oxindole carbamates,exemplified by the preparation of Intermediate 87, ethyl2′,4-dioxospiro[cyclohexane-1,3′-indole]-1′(2′H)-carboxylate

To a solution of spiro [cyclohexane-1,3′-indoline]-2′,4-dione (100 mg,0.5 mmol) and Et₃N (200 μL, 1.4 mmol) in DCM (5 mL) was added ethylchloroformate (60 μL, 0.6 mmol) at 0° C. and the reaction mixturestirred at rt for 1 h. The mixture was then partitioned between cold H₂O(25 mL) and DCM (50 mL) and the aqueous layer further extracted with DCM(2×50 mL). Combined organics were dried (Na₂SO₄) and the solvent removedin vacuo. The crude product was purified by column chromatography(normal-phase silica, 0 to 6% MeOH in DCM) to give ethyl2′,4-dioxospiro[cyclohexane-1,3′-indoline]-1′-carboxylate (117 mg, 87%)as a reddish gum.

The data for Intermediate 87 are in Table 2

Route 10

Typical procedure for the preparation of oxindoles from fluoropyridines,exemplified by the preparation of Intermediate 90,4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

To dimethyl malonate (8.0 mL, 70.0 mmol) in DMF (10 mL) in a sealed tubeat 0° C. was added potassium t-butoxide (4.1 g, 36.9 mmol) and thereaction mixture stirred for 10 min at 90° C. The mixture was thencooled to rt before addition of 3-fluoro-2-nitropyridine (2.5 g, 17.1mmol) and heating at 90° C. for 2 h. The reaction mixture was pouredinto cold 5% aq. HCl (100 mL) and the organic layer extracted with EtOAc(50 mL). The aqueous layer was further extracted with EtOAc (2×100 mL),combined organics dried (Na₂SO₄) and the solvent removed in vacuo. Thecrude product was purified using column chromatography (normal phasesilica, 0 to 18% EtOAc in hexane) to give dimethyl2-(2-nitropyridin-3-yl)malonate (3.0 g, 67%) as yellow liquid.

LCMS (Method F): m/z 255 (M+H)⁺ (ES⁺), at 1.87 min, UV active.

To dimethyl 2-(2-nitropyridin-3-yl) malonate (5.8 g, 22.8 mmol) and37-41% formalin (43.5 mL) in a sealed tube at rt was added a solution ofK₂CO₃ (4.7 g, 34.0 mmol) in water (17.4 mL). The reaction mixture wasstirred for 2 h at 60° C., diluted with ice cold water (250 mL),extracted with EtOAc (250 mL) and the aqueous layer further extractedwith EtOAc (2×150 mL). Combined organics were dried (Na₂SO₄) and thesolvent removed in vacuo. The crude product was purified by columnchromatography (normal phase silica, 0 to 14% EtOAc in hexane) to givemethyl 2-(2-nitropyridin-3-yl)acrylate (1.5 g, 31%) as a yellow liquid.

LCMS (Method F): m/z 209 (M+H)⁺ (ES⁺), at 1.87 min, UV active.

Methyl 2-(2-nitropyridin-3-yl) acrylate (1.48 g, 7.11 mmol) and2-trimethylsilyloxy 1,3-butadiene (1.86 g, 13.09 mmol) in xylene (10 mL)were stirred for 20 h at 160° C. in a sealed tube. The resultingreaction mixture was cooled to rt before addition of p-toluene sulfonicacid monohydrate (1.08 g, 5.68 mmol) and further heating at 70° C. for 4h. The reaction mixture was diluted with ice cold water (200 mL),extracted with EtOAc (200 mL) and the aqueous layer further extractedwith EtOAc (2×100 mL). Combined organics were dried (Na₂SO₄), thesolvent was removed in vacuo and the crude product purified by columnchromatography (normal phase silica, 0 to 10% EtOAc in hexane) to givemethyl 1-(2-nitropyridin-3-yl)-4-oxocyclohexane-1-carboxylate (0.40 g,20%) as a yellow liquid.

LCMS (Method F): m/z 279 (M+H)⁺ (ES⁺).

To methyl 1-(2-nitropyridin-3-yl)-4-oxocyclohexane-1-carboxylate (146mg, 0.52 mmol) in EtOAc (7 mL) was added Raney-Ni (146 mg, w/w) under N₂and the reaction mixture stirred for 24 h. The reaction mixture wasfiltered through celite, the filtrate concentrated in vacuo and theresidue triturated in diethyl ether to give spiro [cyclohexane-1,3′-pyrrolo [2, 3-b] pyridine]-2′,4(1′H)-dione (60 mg, 53%) as anoff-white solid.

The data for Intermediate 90 are in Table 2

Route 11

Typical procedure for the preparation of spiro oxindoles from thecorresponding oxindole, exemplified by the preparation of Intermediate93,5′-chloro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

5-Chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.00 g, 5.9 mmol),potassium t-butoxide (0.67 g, 5.9 mmol) and DMSO (5 mL) were heated at45° C. before addition of methyl acrylate (1.66 mL, 18.3 mmol) dropwiseover 20 min. The reaction mixture was stirred for 30 min at 45° C.before addition of potassium t-butoxide (1.33 g, 11.9 mmol) whilst thereaction temperature was maintained below 55° C. The reaction mixturewas then heated at 100° C. for 2 h before addition of water and furtherstirring at 85° C. for 4 h. The mixture was cooled to rt and allowed tostir for 16 h, diluted with ice cold water (100 mL) and extracted withEtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2×50mL), combined organics dried (Na₂SO₄), the solvent removed in vacuo andthe crude product purified using column chromatography (normal phasesilica, 0 to 30% EtOAc in hexane) to give methyl5′-chloro-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate(0.45 g, 25%) as a white solid.

LCMS (Method F): m/z 309 (M+H)⁺ (ES⁺), at 2.02 min, UV active.

To a solution of methyl5′-chloro-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate(450 mg, 1.5 mmol) in THF/H₂O 2:1 (12 mL) at rt was added potassiumt-butoxide (205 mg, 1.8 mmol) and the reaction heated to 105° C. for 5h. The reaction was cooled to rt before addition of water and extractionwith EtOAc (2×200 mL). Combined organics were dried (Na₂SO₄) and thesolvent removed in vacuo to yield5′-chlorospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione(210 mg, 57%) as white solid. The crude product was taken on directly tothe next step.

The data for Intermediate 93 are in Table 2

Route 12

Typical procedure for the preparation of spiro oxindoles, exemplified bythe preparation of Intermediate 95,5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione

To a stirred solution of diethyl malonate (8.7 mL, 57.3 mmol) in dry THF(300 mL), sodium hydride (2.3 g, 60% w/w in mineral oil, 57.3 mmol) wasadded portionwise at 0° C. and stirred for 1 h. The reaction mixture wasbrought to rt and 2,4-dichloro-5-nitropyridine (10.0 g, 52.0 mmol) wasadded and refluxed for 14 h. After cooling to 0° C., the reactionmixture was carefully quenched with ice cold water and extracted withEtOAc (3×200 mL). The organic layers were combined, washed with brine,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified byflash column chromatography [normal phase, silica gel (100-200 mesh),gradient 10% to 15% EtOAc in hexane] to give diethyl2-(2-chloro-5-nitropyridin-4-yl)malonate (11.1 g, 68%) as a yellowliquid.

MS (ESI −ve): 315

To a stirred solution of diethyl2-(2-chloro-5-nitropyridin-4-yl)malonate (6.1 g, 19.3 mmol) in MeOH (50mL) was added sodium methoxide (48.3 mL, 2 M in MeOH, 96.6 mmol)dropwise at 0° C. The reaction mixture was stirred at rt for 16 h. Aftercompletion, the volatiles were removed in vacuo, water (100 mL) wasadded and the aqueous layer extracted with EtOAc (3×200 mL). The organiclayers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography [normal phase, silica gel (100-200 mesh), gradient 2% to5% EtOAc in hexane] to give methyl2-(2-methoxy-5-nitropyridin-4-yl)acetate (2.0 g, 46%) as a yellow solid.

MS (ESI +ve): 227

To a solution of methyl 2-(2-methoxy-5-nitropyridin-4-yl)acetate (6.1 g,26.9 mmol) in toluene (100 mL), paraformaldehyde (2.3 g, 75.0 mmol),K₂CO₃ (11.1 g, 80.3 mmol) and catalytic tetrabutyl ammonium iodide (0.3g) were added and refluxed for 30 min. The reaction mixture was cooledto rt, filtered through a pad of celite and washed with EtOAc (100 mL).Water (50 mL) was added to the filtrate and the organic layer wasseparated. The aqueous layer was extracted with EtOAc (2×50 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was triturated with Et₂O to givemethyl 2-(2-methoxy-5-nitropyridin-4-yl)acrylate (4.0 g, 62%) as a darkbrown solid. This was used for the next step without furtherpurification.

MS (ESI +ve): 239.

To a suspension of methyl 2-(2-methoxy-5-nitropyridin-4-yl)acrylate (1.0g, 4.2 mmol) in xylene (65 mL), 2-(trimethylsilyloxy)-1,3-butadiene (3.3mL, 18.9 mmol) was added at rt and the reaction mixture was refluxed for24 h. After cooling to rt, catalytic pTSA (0.1 g) was added and themixture stirred at rt for 1 h. The reaction mixture was diluted withEtOAc (50 mL), water (30 mL) was added and the organic layer wasseparated. The aqueous layer was extracted with EtOAc (2×200 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give crude methyl1-(2-methoxy-5-nitropyridin-4-yl)-4-oxocyclohexane-1-carboxylate (1.2 g,93%) as a light brown semi solid. The crude product was used for thenext step without further purification.

MS (ESI +ve): 309.

To a solution of methyl1-(2-methoxy-5-nitropyridin-4-yl)-4-oxocyclohexane-1-carboxylate (800mg, 2.6 mmol) in acetic acid (15 mL), iron powder (695 mg, 12.4 mmol)was added at rt and refluxed for 3 h. The reaction mixture was cooled tort, filtered through a pad of celite and washed with ethanol (50 mL).After removing the volatiles from the filtrate, water (50 mL) was addedand organics extracted with EtOAc (3×25 mL). The organic layers werecombined and washed with brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash column chromatography [normalphase, silica gel (100-200 mesh), gradient 2% to 3% EtOAc in hexane] togive5′-methoxyspiro-[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione,(500 mg, 73% over 2 steps) as a yellow solid.

The data for Intermediate 95 are in Table 2

Route 13

Typical procedure for the preparation of spiro oxindoles, exemplified bythe preparation of Intermediate 97,5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione

To NaH (4.24 g, 60% w/w in mineral oil, 106.0 mmol) in THF (80 mL) wasadded diethyl malonate (16.16 mL, 106.0 mmol) dropwise at 0° C. and thereaction mixture stirred for 1 h. 2-chloro-6-methoxy-3-nitropyridine(10.00 g, 53.0 mmol) in THF (20 mL) was added dropwise and the resultingmixture stirred at 80° C. for 16 h. The reaction mixture was partitionedbetween cold H₂O (250 mL) and EtOAc (100 mL), the aqueous layer furtherextracted with EtOAc (2×100 mL), combined organics dried (Na₂SO₄) andthe solvent removed in vacuo. The crude product was purified by columnchromatography (normal phase silica, 0 to 20% EtOAc in hexane) to givediethyl 2-(6-methoxy-3-nitropyridin-2-yl)malonate (13.21 g, 80%) as alight green solid.

LCMS (Method F): m/z 313 (M+H)⁺ (ES⁺), at 2.43 min, UV active.

Diethyl 2-(6-methoxy-3-nitropyridin-2-yl) malonate (13.0 g, 41.6 mmol),LiCl (4.4 g, 104.0 mmol), and H₂O (0.67 mL, 37.2 mmol) were dissolved inDMSO (130 mL) and the mixture stirred at 100° C. for 16 h. The reactionmixture was partitioned between cold H₂O (150 mL) and EtOAc (75 mL), theaqueous layer further extracted with EtOAc (2×75 mL), combined organicsdried (Na₂SO₄) and the solvent removed in vacuo. The crude product waspurified by column chromatography (normal phase silica, 0 to 12% EtOAcin hexane) to give ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acetate (1.7g, 17%) as a yellow gum.

LCMS (Method F): m/z 241 (M+H)⁺ (ES⁺), at 2.33 min, UV active.

To copper acetate monohydrate (0.12 g, 0.6 mmol), potassium acetate(0.92 g, 9.4 mmol) paraformaldehyde (1.87 g, 62.3 mmol) and ethyl2-(6-methoxy-3-nitropyridin-2-yl) acetate (1.50 g, 6.2 mmol) under N₂was added acetic acid (5 mL) and the solution degassed for 15 min,before stirring at 100° C. for 2 h. The reaction mixture was dilutedwith ice cold water (20 mL) and basified with aq. NaOH. The reactionmixture was partitioned between cold H₂O (25 mL) and EtOAc (20 mL), theaqueous layer further extracted with EtOAc (2×20 mL), combined organicsdried (Na₂SO₄) and the solvent removed in vacuo. The crude product waspurified by column chromatography (normal-phase silica, 0 to 10% EtOAcin hexane) to give ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acrylate (1.50g, 96%) as a yellow gum.

LCMS (Method F): m/z 253 (M+H)⁺ (ES⁺), at 2.41 min, UV active.

To a degassed solution of ethyl 2-(6-methoxy-3-nitropyridin-2-yl)acrylate (1.50 g, 5.9 mmol) in xylene (5 mL) was added2-trimethylsilyloxyl-1,3-butadiene (3.1 mL, 17.8 mmol) and the mixturestirred at 150-160° C. for 21 h. To the mixture was then added pTSA(0.52 g, 3.0 mmol) with further heating at 100° C. for 4 h. The reactionmixture was partitioned between cold H₂O (25 mL) and EtOAc (15 mL), theaqueous layer further extracted with EtOAc (2×15 mL), combined organicsdried (Na₂SO₄) and the solvent removed in vacuo. The crude product waspurified by column chromatography (normal phase silica, 0 to 20% EtOAcin hexane) to give ethyl1-(6-methoxy-3-nitropyridin-2-yl)-4-oxocyclohexane-1-carboxylate (0.83g, 43%) as a yellow gum.

LCMS (Method F): m/z 323 (M+H)⁺ (ES⁺), at 2.31 min, UV active.

A mixture of ethyl1-(6-methoxy-3-nitropyridin-2-yl)-4-oxocyclohexane-1-carboxylate (0.55g, 1.7 mmol), Fe Powder (0.48 g, 8.5 mmol), NH₄Cl (0.27 g, 5.1 mmol),H₂O (2 mL) and conc. HCl (0.50 mL) in ethanol (8 mL) was stirred at 90°C. for 16 h in a sealed tube. The reaction mixture was partitionedbetween cold H₂O (25 mL) and EtOAc (15 mL), the aqueous layer furtherextracted with EtOAc (2×15 mL), combined organics dried (Na₂SO₄) and thesolvent removed in vacuo to give5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione(320 mg, 76%) as a yellow solid.

The data for Intermediate 97 are in Table 2

Route 14

Typical procedure for the preparation of piperidines, exemplified by thepreparation of

Intermediate 103,4-[4-(aminomethyl)piperidin-1-yl]spiro[cyclohexane-1,3′-indol]-2′(1′H)—O-onedi-trifluoroacetic acid salt, mixture of two isomers

A solution of spiro[cyclohexane-1,3′-indoline]-2′,4-dione (200 mg, 0.9mmol), tert-butyl piperidin-4-ylmethylcarbamate (218 mg, 1.0 mmol),ZnCl₂ (37 mg, 0.3 mmol) and Et₃N (470 mg, 4.6 mmol) in MeOH (10 mL) wasstirred at 50° C. for 1 h. The mixture was cooled to 0° C. beforeportionwise addition of NaBH₃CN (243 mg, 3.9 mmol) and further stirringat 50° C. for 7 h. The reaction mixture was concentrated in vacuo, theresidue partitioned between H₂O (80 mL) and EtOAc (50 mL), the aqueouslayer extracted with EtOAc (2×50 mL), combined organics dried (Na₂SO₄)and the solvent removed in vacuo. The residue was purified by columnchromatography (normal silica, mesh size: 60-120, 0% to 2% MeOH in DCM)to give tert-butyl(1-(2′-oxospiro[cyclohexane-1,3′-indoline]-4-yl)piperidin-4-yl)methylcarbamate(300 mg, 78%) as a yellow gum as a mixture of isomers.

LCMS (Method F): m/z 414 (M+H)⁺ (ES⁺), at 1.78 min (isomer 1) and 1.82min (isomer 2), UV active.

To a solution of tert-butyl(1-(2′-oxospiro[cyclohexane-1,3′-indoline]-4-yl)piperidin-4-yl)methylcarbamate(300 mg, 0.7 mmol) in DCM (20 mL) under N₂ at 0° C. was added TFA (248mg, 2.2 mmol) and the reaction mixture warmed to rt over 2 h. Thesolvent was removed in vacuo to give4-(4-(aminomethyl)piperidin-1-yl)spiro[cyclohexane-1,3′-indolin]-2′-onedi-TFA salt (200 mg, 53%) as a colorless liquid as a mixture of isomers.

The data for Intermediate 103 are in Table 2

Route 15

Typical procedure for the preparation of 1,4-diazepanes, exemplified bythe preparation of Intermediate 107, 1-(1,4-diazepan-1-yl)but-2-en-1-onetrifluoroacetic acid salt

To a solution of tert-butyl 1,4-diazepane-1-carboxylate (1.50 g, 7.5mmol) and Et₃N (2.28 g, 22.5 mmol) in DCM (5 mL) at 0° C. was addedcrotonyl chloride (1.18 g, 11.3 mmol) and the reaction mixture stirredat rt for 1 h. The mixture was partitioned between cold H₂O (25 mL) andEtOAc (15 mL), the aqueous layer further extracted with EtOAc (2×15 mL),combined organics dried (Na₂SO₄) and the solvent removed in vacuo toyield tert-butyl 4-but-2-enoyl-1,4-diazepane-1-carboxylate (1.80 g, 90%)as a brown liquid.

LCMS (Method F): m/z 269 (M+H)⁺ (ES⁺), at 1.95 min UV active.

To a solution of tert-butyl 4-but-2-enoyl-1,4-diazepane-1-carboxylate(1.8 g, 6.7 mmol) in DCM (20 mL) was added TFA (10 mL) at 0° C. and thereaction mixture stirred for 3 h at rt. The reaction mixture wasconcentrated in vacuo and triturated with acetone (3×10 mL) to give1-(1,4-diazepan-1-yl)but-2-en-1-one trifluoroacetic acid salt (1.0 g,53%) as a brown liquid.

The data for Intermediate 107 are in Table 2

Route 16

Typical procedure for the preparation of spiro oxindoles, exemplified bythe preparation of Intermediate 99,4H-spiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione

To NaH (60% in mineral oil, 51 g, 1.3 mol) in THF (300 mL) at 0° C. wasadded diethyl malonate (202 g, 1.3 mol) dropwise whilst the temperaturewas maintained between 0-10° C. and the resulting mixture stirred at0-10° C. for 1 h until hydrogen emission ceased. A solution of2-chloro-3-nitropyridine (100 g, 0.6 mol) in dry THF (300 mL) was addeddropwise and the resulting solution refluxed overnight. The solvent wasremoved in vacuo, the residue dissolved in EtOAc (10 L), filtered, theorganic phase washed with water (5×1 L), dried over Na₂SO₄ andconcentrated in vacuo to afford crude diethyl(3-nitropyridin-2-yl)-malonate (50 g, 28%) which was used in the nextstep without purification

To a solution of diethyl (3-nitropyridin-2-yl)-malonate (12.5 g, 44mmol) in DMSO (150 mL) at rt under N₂ was added water (0.8 mL, 44 mmol)and lithium chloride (4.7 g, 110 mmol) and the reaction mixture heatedat 100° C. for 12 h. A second batch of lithium chloride (1.0 g, 24 mmol)was then added and the mixture heated for 5 h, cooled to rt and dilutedwith brine (150 mL). The aqueous layer was then extracted with EtOAc(3×275 mL), combined organics dried over Na₂SO₄, the solutionconcentrated in vacuo and the resulting solid triturated with diethylether to afford ethyl 2-(3-nitropyridin-2-yl)acetate (8.6 g, 93%).

To a solution of ethyl 2-(3-nitropyridin-2-yl)acetate (50 g, 0.24 mol)in benzene (1 L) was added acetic acid (5 mL), piperidine (5 mL) and1,3,5-trioxane (62 g, 0.69 mol). The reaction flask was fitted with aDean-Stark trap and the yellow solution heated under reflux for 24 h. Tothe hot solution was added further 1,3,5-trioxane (60 g) and theresulting mixture heated for an additional 24 h. The solvents wereremoved in vacuo and the reside purified by column chromatography(silica, hexane/EtOAc=9:1) to afford ethyl2-(3-nitropyridin-2-yl)acrylate (34 g, 64%).

A mixture of ethyl 2-(3-nitropyridin-2-yl)acrylate (5.0 g, 22.5 mmol),2-trimethylsilyloxy-1,3-butadiene (4.8 g, 33.7 mmol) and xylene (50 mL)was heated in a sealed tube at 130° C. for 20 h. The mixture was thencooled to rt before addition of p-toluenesulfonic acid monohydrate (0.5g, 2.6 mmol) and further stirring for 2 h. The mixture was then dilutedwith EtOAc (100 mL), washed with water (1×50 mL) and brine (1×50 mL),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica, EtOAc/hexane, 1:9 to EtOAc/hexane, 2:3)to afford ethyl 1-(3-nitropyridin-2-yl)-4-oxocyclohexanecarboxylate (5.0g, 76%).

To ethyl 1-(3-nitropyridin-2-yl)-4-oxocyclohexanecarboxylate (2.5 g, 8.6mmol) in EtOH (80 mL) was added NH₄Cl (0.1 g, 1.9 mmol), H₂O (0.5 mL),conc. HCl (0.5 mL) and iron powder (2.5 g, 44.6 mmol). The reactionmixture was heated at reflux for 2 h, neutralized with aq. sodiumhydroxide (2N) to pH 8 and filtered. The filtrate was concentrated underreduced pressure and the resulting residue was triturated with H₂O toyield the desired product (1.0 g, 54%).

The data for Intermediate 99 are in Table 2

Route 17

Typical procedure for the preparation of spiro oxindoles, exemplified bythe preparation of Intermediate 113,5′-methoxy-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione

To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (1.00 g, 6.8 mmol)in t-BuOH (60 mL), pyridinium tribromide (6.48 g, 20.3 mmol) was addedand the reaction mixture was stirred at rt for 16 h. The reactionmixture was concentrated in vacuo and the residue was dissolved in EtOAc(50 mL). Water (50 mL) was added and the organic layer was separated.The aqueous layer was extracted with EtOAc (2×50 mL). The organic layerswere combined and washed with sat. aq. NaHCO₃ solution (20 mL), brine(20 mL), dried (Na₂SO₄) and concentrated in vacuo. The residue wastriturated with diethyl ether (1×10 mL) to give3,3-dibromo-5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.5 g,69%) as a brown solid. This product was used for the next step withoutfurther purification.

To a solution of3,3-dibromo-5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g,9.3 mmol) in AcOH (60 mL), zinc dust (6.1 g, 93.2 mmol) was added andstirred at rt for 2 h. The reaction mixture was filtered through a padof celite and washed with EtOAc (2×100 mL). The filtrate wasconcentrated in vacuo and the residue was dissolved in EtOAc (100 mL),washed with 10% aq Rochelle salt (20 mL), brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was triturated with diethyl ether(2×20 mL) to give 5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(0.9 g, 59%) as a brown solid. This crude product was used for the nextstep without further purification.

MS (ESI +ve): 165

To a solution of 5-methoxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one(2.00 g, 12.2 mmol) in DMSO (20 mL), ^(t)BuOK (0.54 g, 4.8 mmol) wasadded at rt and stirred for 10 min. Methyl acrylate (3.0 mL, 33.1 mmol)was slowly added and the reaction mixture was stirred at 45° C. for 1 h.The reaction mixture was quenched with AcOH (3 mL) and poured intoice-water (100 mL) and extracted with EtOAc (3×20 mL). The organiclayers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography [normal phase, silica gel (100-200 mesh), gradient 1% to5% EtOAc in hexane] to give trimethyl3,3′,3″-(5-methoxy-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,3,3-triyl)tripropionate(1.8 g, 35%) as a liquid.

MS (ESI +ve): 423

To a solution of trimethyl3,3′,3″-(5-methoxy-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,3,3-triyl)tripropionate(500 mg, 1.18 mmol) in DMSO (10 mL), ^(t)BuOK (500 mg, 4.45 mmol) wasadded at rt and the reaction mixture was heated to 75° C. for 1 h.

After cooling to rt, the reaction mixture was quenched with AcOH (5 mL),poured into ice-water (50 mL) and extracted with EtOAc (3×15 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give methyl5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate(300 mg, 83%) as a pale yellow solid. This crude product was used forthe next step without further purification.

MS (ESI +ve): 305

To a solution of methyl5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate(800 mg, 2.63 mmol) in MeOH (20 mL), aq. KOH (1 M, 10 mL) was added atrt and the reaction mixture was refluxed for 7 h. After removal ofvolatiles, water (20 mL) was added to the residue and extracted withEtOAc (3×20 mL). The organic layers were combined and washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give methyl5′-methoxy-2′,4-dioxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate(503 mg, 78%) as a pale yellow solid. This crude product was used forthe next step without further purification.

The data for Intermediate 113 are in Table 2

Route 18

Typical procedure for the preparation of spiro oxindoles, exemplified bythe preparation of Intermediate 116,1′,2′-dihydro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one

To a solution of 2-(2-methylpyridin-3-yl)acetonitrile (1.0 g, 6.6 mmol)and methyl acrylate (1.8 mL, 19.9 mmol) in THF (10 mL) at 0° C. wasadded potassium tert-butoxide (8.6 mL, 8.6 mmol, 1 M in THF) and theresulting reaction mixture stirred at 25° C. for 3 h. The mixture waspartitioned between H₂O (100 mL) and EtOAc (80 mL), the aqueous layerfurther extracted with EtOAc (2×80 mL), combined organics dried (Na₂SO₄)and the solvent removed in vacuo. The residue was purified by columnchromatography (normal silica, mesh size: 60-120, 0% to 0.5% MeOH inDCM) to give methyl5-(2-chloropyridin-3-yl)-5-cyano-2-oxocyclohexane-1-carboxylate (1.2 g,63%) as a yellow liquid.

LCMS (Method F): m/z 293 (M+H)⁺ (ES⁺), at 1.97 min UV active.

To a solution of methyl5-(2-chloropyridin-3-yl)-5-cyano-2-oxocyclohexane-1-carboxylate (1.20 g,4.1 mmol) in THF (5 mL) was added potassium tert-butoxide (1.03 g, 9.2mmol) in water (10 mL), and the resulting mixture stirred at 80° C. for17 h. The solvents were removed in vacuo and the residue partitionedbetween H₂O (120 mL) and EtOAc (80 mL). The aqueous layer was extractedwith EtOAc (2×80 mL), combined organics dried (Na₂SO₄) and the residuepurified by column chromatography (normal silica, mesh size: 60-120,1.0% to 1.5% MeOH in DCM) to give1-(2-chloropyridin-3-yl)-4-oxocyclohexane-1-carbonitrile (800 mg, 83%)as a yellow solid.

LCMS (Method H): m/z 235 (M+H)⁺ (ES⁺), at 7.19 min UV active.

To a solution of1-(2-chloropyridin-3-yl)-4-oxocyclohexane-1-carbonitrile (800 mg, 3.4mmol) in toluene (10 mL) was added p-toluene sulfonic acid (152 mg, 0.9mmol) and ethylene glycol (500 μL, 9.0 mmol) and the resulting mixturestirred at 100° C. for 4 h. The solvents were removed in vacuo and theresidue partitioned between H₂O (100 mL) and EtOAc (70 mL). The aqueouslayer was extracted with EtOAc (2×70 mL), combined organics dried(Na₂SO₄) and the residue purified by column chromatography (normalsilica, mesh size: 60-120, 1.0% to 1.5% MeOH in DCM) to give8-(2-chloropyridin-3-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (900mg, 95%) as a yellow solid.

LCMS (Method F): m/z 279 (M+H)⁺ (ES⁺), at 1.99 min UV active.

To 8-(2-chloropyridin-3-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile(1.0 g, 3.6 mmol) in THF (10 mL) at 0° C. was added LiAlH₄ (9.9 mL, 9.9mmol, 1 M in THF) dropwise and the resulting mixture stirred at 25° C.for 3 h. The reaction mixture was partitioned between H₂O (100 mL) andEtOAc (70 mL), the aqueous layer extracted with EtOAc (2×70 mL),combined organics dried (Na₂SO₄) and the solvent removed in vacuo. Theresidue was purified by column chromatography (normal silica, mesh size:60-120, 2.0% to 3.5% MeOH in DCM) to give1,2-dihydrodispiro[pyrrolo[2,3-b]pyridine-3,1′-cyclohexane-4′,2″-[1,3]dioxolane](700 mg, 79%) as a light yellow solid.

LCMS (Method F): m/z 247 (M+H)⁺ (ES⁺), at 1.53 min UV active.

A solution of(1,2-dihydrodispiro[pyrrolo[2,3-b]pyridine-3,1′-cyclohexane-4′,2″-[1,3]dioxolane](700 mg, 2.8 mmol) in 6 N HCl (10 mL) was stirred at 50° C. for 16 h.The solvent was then removed in vacuo, and the residue partitionedbetween H₂O (80 mL) and EtOAc (50 mL). The aqueous layer was extractedwith EtOAc (2×50 mL) combined organics dried (Na₂SO₄) and the solventremoved in vacuo. The crude product was purified by columnchromatography (normal silica, mesh size: 60-120, 3.0% to 3.5% MeOH inDCM) to give1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one (500mg, 87%) as a yellow solid.

The data for Intermediate 116 are in Table 2

Route 19

Typical procedure for the preparation of sulfonamides, exemplified bythe preparation of Intermediate 117,1′-(methylsulfonyl)-1′,2′-dihydro-4H-spiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one

To a solution of1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one (400mg, 2.0 mmol) and Et₃N (600 μL, 4.3 mmol) in DCM (5 mL) at 0° C. wasadded methanesulfonyl chloride (200 μL, 2.6 mmol) dropwise and theresulting mixture stirred at 25° C. for 1 h. The reaction mixture waspartitioned between H₂O (70 mL) and EtOAc (50 mL), the aqueous layerfurther extracted with EtOAc (2×50 mL), combined organics dried (Na₂SO₄)and the solvent removed in vacuo. The crude residue was purified bycolumn chromatography (normal silica, mesh size: 60-120, 0.5% to 1.0%MeOH in DCM) to give1′-(methylsulfonyl)-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-one(400 mg, 72%) as a yellow gum.

The data for Intermediate 117 are in Table 2

Route 20

Typical procedure for the preparation of ethyl carbamates, exemplifiedby the preparation of Intermediate 6, ethyl2,8-diazaspiro[4.5]decane-2-carboxylate

To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate(0.96 g, 4 mmol) in DCM (25 mL) at rt was added Et₃N (2.78 mL, 20 mmol)and ethyl chloroformate (0.71 mL, 7 mmol) and the mixture stirred at rtfor 16 h. Sat. aq. NaHCO₃ (10 mL) was then added and the layersseparated. The aqueous layer was extracted with DCM (4×25 mL), combinedorganics dried through a Biotage Phase Separator cartridge and thesolvent removed in vacuo. To the residue was added ether (50 mL) and 4 MHCl in dioxane (5 mL) and the mixture stirred at rt for 16 h. Thesolvent was then removed in vacuo, the residue dissolved in MeOH (8 mL)and to the solution was added K₂CO₃ (607 mg) as a solution in water (2mL) and the mixture stirred at rt for 1 h. The solvent was then removedin vacuo and the residue suspended in DCM, filtered and the solventremoved in vacuo to yield Ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate(0.23 g, 27%).

The data for Intermediate 6 are in Table 2

Route 21 Typical procedure for the preparation of 1,2,4-oxadiazoles asexemplified by the preparation of Intermediate 126,(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine hydrochloridesalt

di-tert-Butyl dicarbonate (1.25 g, 5.75 mmol) and DIPEA (2.61 mL, 15.0mmol) were added to a solution of (1S,3R)-3-aminocyclopentanecarboxylicacid (0.646 g, 5.0 mmol) in 1,4-dioxane (5 mL) and water (5 mL) and theresulting mixture was stirred at RT for 3 h. The reaction mixture wasacidified to pH˜2 using 1 M aqueous HCl and extracted with DCM (×4). Thecombined organic extracts were passed through a phase separatorcartridge and concentrated in-vacuo to give (1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.13 g,99%).

¹H NMR (400 MHz, CDCl₃) δ: 1.44 (s, 9H), 1.56-2.06 (m, 5H), 2.16-2.33(m, 1H), 2.79-2.93 (m, 1H), 3.87-4.18 (m, 1H), 4.86 (br. s., 1H). Oneexchangeable proton not observed.

Triethylamine (2.1 mL, 15.0 mmol) and HATU (2.09 g, 5.5 mmol) were addedto a solution of(1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.13g, 5.0 mmol) and N-hydroxyethanimidamide (0.37 g, 5.0 mmol) in DCM (25mL) and the resulting mixture was stirred at RT overnight. The reactionmixture was diluted with sat. aq. NaHCO₃ and extracted with DCM (×3).The combined organic phases were passed through a phase separatorcartridge and concentrated in-vacuo to give the crude uncyclisedproduct, which was immediately dissolved in THF (50 mL), treated withCs₂CO₃ (3.26 g, 10 mmol) and heated at reflux at 70° C. overnight. Thereaction mixture was concentrated to remove the THF and the residue waspartitioned between sat. aq. NaHCO₃ and EtOAc. The phases were separatedand the aqueous phase was extracted further with EtOAc (×2). Thecombined organic phases were passed through a phase separator cartridgeand concentrated. The crude residue was purified by flash chromatography(normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to givetert-butyl[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]carbamate (1.15 g,87%).

LCMS (Method C): m/z 168 [M−BOC+H]⁺ (ES⁺), at 1.23 min, UV active.

tert-Butyl[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]carbamate (1.15 g,4.32 mmol) was dissolved in DCM (22 mL) and treated with 4.0 M HCl in1,4-dioxane (5.4 mL, 21.6 mmol). The resulting solution was stirred atRT overnight, then diluted with diethyl ether to precipitate a solidthat was collected by filtration to give(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine hydrochloridesalt (0.655 g, 91%) as a white solid.

The data for Intermediate 126 are in Table 2.

Route 22

Typical procedure for the preparation of 1,2,4-oxadiazoles asexemplified by the preparation of Intermediate 131,6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptanetrifluoroacetic acid salt

Triethylamine (1.67 mL, 12.0 mmol) and HATU (1.67 g, 4.4 mmol) wereadded to a solution of2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (0.965g, 4.0 mmol) and 2,2,2-trifluoro-N-hydroxyethanimidamide (0.512 g, 4.0mmol) in THF (20 mL) and the resulting mixture was stirred at RT for 4 hthen heated at reflux at 80° C. overnight. The reaction mixture wasconcentrated to remove the THF and the residue was partitioned betweensat. aq. NaHCO₃ (containing some Na₂CO₃) and DCM. The phases wereseparated and the aqueous phase was extracted further with DCM (×2). Thecombined organic phases were passed through a phase separator cartridgeand concentrated. The crude residue was purified by flash chromatography(normal silica, mesh size: 60-120, 0% to 10% MeOH in DCM) to give impuretert-butyl6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate(2.05 g, >100%).

LCMS (Method C): m/z 278 [M−^(t)Bu+H]⁺ (ES⁺), at 1.59 min, UV active.

tert-Butyl6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptane-2-carboxylate(2.05 g crude, assumed 4.0 mmol) was dissolved in DCM (20 mL) andtreated with TFA (5 mL). The resulting solution was stirred at RTovernight, then concentrated in-vacuo. The residue was re-dissolved inDCM and concentrated to give6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3]heptanetrifluoroacetic acid salt (>100%).

The data for Intermediate 131 are in Table 2.

Route 23

Typical procedure for the preparation of 1,2,4-oxadiazoles asexemplified by the preparation of Intermediate 133,2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane hydrochloridesalt

60% Sodium hydride suspension in mineral oil (160 mg, 4.0 mmol) wasadded to a solution of 6-tert-butyl 2-methyl6-azaspiro[3.4]octane-2,6-dicarboxylate (0.539 g, 2.0 mmol),N-hydroxyethanimidamide (0.148 g, 2.0 mmol) and triethylamine (0.60 mL,4.0 mmol) in THF (20 mL). The reaction mixture was heated at reflux at80° C. overnight, then cooled, diluted with water and extracted withEtOAc (×3). The combined organic phases were passed through a phaseseparator cartridge and concentrated. The crude residue was purified byflash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOHin DCM) to give tert-butyl2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.384 g, 65%).

LCMS (Method C): m/z 238 [M-^(t)Bu+H]⁺ (ES⁺), at 1.43 min, UV active.

tert-Butyl2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.384 g, 1.3 mmol) was dissolved in DCM (13 mL) and treated with 4.0 MHCl in 1,4-dioxane (1.7 mL, 6.5 mmol). The resulting solution wasstirred at RT overnight, then concentrated in-vacuo to give2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octane hydrochloridesalt (0.282 g, 94%).

The data for Intermediate 133 are in Table 2.

Route 24

Typical procedure for the preparation of 1,2,4-oxadiazoles asexemplified by the preparation of Intermediate 135,(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine

Triethylamine (36 mL, 254 mmol) and di-tert-butyl dicarbonate (41.6 mL,191 mmol) were added to a solution of ethyl piperidine-3-carboxylate(20.0 g, 127 mmol) in DCM (150 mL), pre-cooled to 0° C. The resultingreaction mixture was stirred at 0° C. for 2 h. The solvents were thenremoved in-vacuo, the residue was partitioned between H₂O (400 mL) andEtOAc (250 mL) and the layers were separated. The aqueous layer wasfurther extracted with EtOAc (2×250 mL), and the combined organic layerswere dried (Na₂SO₄) and the solvent was removed in-vacuo to give1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (32.0 g, 98%) as aliquid.

LCMS (Method I): m/z 258 (M+H)⁺ (ES⁺), at 4.93 min, UV active.

1-tert-Butyl 3-ethyl piperidine-1,3-dicarboxylate (30.0 g, 117.0 mmol)was dissolved in THF (200 mL) and treated with N-hydroxyethanimidamide(10.36 g, 140 mmol). The reaction mixture was stirred at 25° C. for 10mins then sodium methoxide (12.6 g, 233 mmol) was added slowly. Theresulting reaction mixture was stirred at 65° C. for 6 h, the solventswere removed in-vacuo, and the residue was partitioned between H₂O (400mL) and EtOAc (300 mL). The layers were separated and the aqueous layerwas further extracted with EtOAc (2×300 mL). The combined organic layerswere dried (Na₂SO₄), the solvent was removed in-vacuo and residue waspurified by column chromatography (Normal neutral activated alumina, 10%to 15% EtOAc in hexane) to give tert-butyl3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (15.80 g, 51%)as a liquid.

LCMS (Method F): m/z 268 (M+H)⁺ (ES⁺), at 2.12 min, UV active.

tert-Butyl 3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate(15.5 g, 58.0 mmol) was dissolved in 1,4-dioxane (40 mL) and cooled to0° C. 4.0 M HCl in 1,4-dioxane (50 mL) was added dropwise and theresulting reaction mixture was stirred at 25° C. for 8 h. The solventswere removed in-vacuo, and residue was purified by triturating withdiethyl ether (3×20 mL) to give3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride salt (9.10 g,77%) as a solid.

LCMS (Method I): m/z 168 (M+H)⁺ (ES⁺), at 2.61 min, UV active.

3-(3-Methyl-1,2,4-oxadiazol-5-yl)piperidine hydrochloride salt (5.0 g,29.9 mmol) was dissolved in a mixture of acetonitrile (250 mL) and MeOH(100 mL). L-Tartaric acid (4.49 g, 29.9 mmol) was added and the mixturewas heated at reflux for 15 mins, then cooled to RT. Acetonitrile (250mL) was added and the mixture was stirred at 25° C. for 16 h. Theprecipitated amine salt was removed by filtration, washed with asolution of MeOH (50 mL) in acetonitrile (125 mL), and dried. The solidwas recrystallized 4 times from a solution of MeOH (50 mL) inacetonitrile 125 mL, isolated by filtration, and dried to give(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine L-tartaric acid salt.The salt was dissolved in sat. aq. NaHCO₃ and extracted with a 10%solution of MeOH in DCM (×3). The combined organic layers were dried(Na₂SO₄) and the solvent was removed in-vacuo to give(3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine (980 mg, 20%) as aliquid.

The data for Intermediate 135 are in Table 2.

Route 25

Typical procedure for the preparation of 1,2,4-oxadiazoles asexemplified by the preparation of Intermediate 137,1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methanaminehydrochloride salt

Triethylamine (1.7 mL, 12.0 mmol) and di-tert-butyl dicarbonate (0.917g, 4.2 mmol) were added to a solution of methyl2-(aminomethyl)cyclopropanecarboxylate hydrochloride salt (0.497 g, 3.0mmol) in DCM (30 mL). The mixture was stirred at RT overnight, thendiluted with sat. aq. NaHCO₃ and extracted with EtOAc (×3). The combinedorganic phases were passed through a phase separator cartridge andconcentrated to give methyl2-{[(tert-butoxycarbonyl)amino]methyl}cyclopropanecarboxylate (0.795 g,>100%).

¹H NMR (400 MHz, CDCl₃) δ: 0.80-0.89 (m, 1H), 1.16-1.24 (m, 1H), 1.45(s, 9H), 1.51-1.65 (m, 2H), 2.96-3.09 (m, 1H), 3.11-3.23 (m, 1H), 3.68(s, 3H), 4.64 (br. s., 1H).

2-{[(tert-Butoxycarbonyl)amino]methyl}cyclopropanecarboxylate (0.688 g,3.0 mmol), N-hydroxyethanimidamide (0.222 g, 3.0 mmol) and triethylamine(0.90 mL, 6.0 mmol) were dissolved in THF (30 mL) and treated with 60%sodium hydride suspension in mineral oil (0.24 g, 6.0 mmol). Theresulting mixture was heated at reflux overnight, then cooled, dilutedwith water and extracted with EtOAc (×3). The combined organic phaseswere passed through a phase separator cartridge and concentrated. Thecrude residue was purified by flash chromatography (normal silica, meshsize: 60-120, 0% to 10% MeOH in DCM) to give tert-butyl{[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}carbamate (0.378g, 50%).

LCMS (Method C): m/z 198 [M−^(t)Bu+H]⁺ (ES⁺), at 1.19 min, UV active.

tert-Butyl{[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}carbamate (0.378g, 1.5 mmol) was dissolved in DCM (15 mL) and treated with 4.0 M HCl in1,4-dioxane (1.9 mL, 7.5 mmol). The resulting solution was stirred at RTovernight, then more 4.0 M HCl in 1,4-dioxane (0.95 mL, 3.8 mmol) wasadded and the mixture was stirred over an additional night. The mixturewas then concentrated in-vacuo and the residue triturated with diethylether to afford a solid that was removed by filtration to give1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methanaminehydrochloride salt (0.134 g, 47%).

The data for Intermediate 137 are in Table 2.

General Synthetic Procedures:

Route A

Typical procedure for the preparation of cyclohexanes via Intermediate32 and

Intermediate 44 as exemplified by the preparation of Example 3-19, ethyl4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate

1-(5-Methoxypyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.20 g, 0.87mmol) and ethyl 1,4-diazepane-1-carboxylate hydrochloride (0.18 g, 1.01mmol) were dissolved in DCM (20 mL) and MeOH (2 mL) and acetic acid (5drops) were added. The reaction mixture was stirred at rt for 4 h andthen cooled to 0° C. STAB (0.73 g, 3.47 mmol) was added portionwise andthe reaction mixture stirred at rt overnight. NaHCO₃(saturated aq., 40mL) was added, and the reaction mixture was stirred at rt for 1 h, thenextracted with DCM (4×40 mL). The organic layers were combined and dried(MgSO₄). The solvents were removed in vacuo to and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 □m, 60 Å, 25 mL per min, gradient 0% to 10% MeOH inDCM]). The residue further purified by Prep HPLC [reverse phase HPLC(X-Bridge, 250×19 mm, 5 um, 19 mL per min, gradient 35% (over 25 min)0.1% NH₃ in MeCN/water] to give ethyl4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate,Example 3-19 isomer 1 (0.05 g, 14.9%) as a pale yellow gum and ethyl4-[4-(5-methoxypyridin-2-yl)-4-cyanocyclohexyl]-1,4-diazepane-1-carboxylate,Example 3-19 isomer 2 (0.03 g, 8.9%) as a pale yellow gum.

The data for Example 3-19 Isomer 2 are in Table 3.

Route B

Typical procedure for the preparation of substituted cyclohexylderivatives via Intermediate 15 and Intermediate 28 as exemplified bythe preparation of Example 1-15, ethyl{(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate

tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (0.75 mL, 2.0 mmol) and1-(5-chloropyridin-2-yl)-4-oxocyclohexanecarbonitrile (0.83 mL, 2.2mmol) were dissolved in DCM (7.5 mL), and acetic acid (5-10 drops) wasadded. The reaction mixture was stirred at rt for 4 h and then cooled to0° C. STAB (0.64 g, 3.0 mmol) was added portionwise and the reactionmixture stirred at rt overnight. NaHCO₃(saturated aq., 30 mL) was added,and the reaction mixture was stirred at rt for 1 h, then extracted withDCM (4×30 mL) and the organic layers were combined and dried (MgSO₄).The solvents were removed in vacuo to give a crude mixture of tert-butyl{(3S)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamatewhich was used directly without further purification. The residue wasdissolved in DCM (10 mL) and cooled to 0° C., trifluoroacetic acid (4mL) was added and the reaction mixture was stirred at rt overnight. Thesolvents were removed in vacuo, the residue was dissolved in toluene (20mL), and then concentrated in vacuo (three times), to give thetrifluoroacetic acid salt of a mixture of4-[(3S)-3-aminopyrrolidin-1-yl]-1-(5-chloropyridin-2-yl)cyclohexanecarbonitrilediastereomers which were used directly without further purification. Aportion of the residue (assumed 0.75 mmol) was dissolved in DCM (8 mL)and NEt₃ (0.52 mL, 3.75 mmol) was added, the reaction mixture was cooledto 0° C. and ethyl chloroformate (0.11 mL, 1.13 mmol) was added. Thereaction mixture was stirred at rt overnight and then partitionedbetween DCM (30 mL) and sat. NaHCO₃ sol. (20 mL), the aqueous layer wasextracted with DCM (3×30 mL) and the organic layers were combined washedwith brine (25 mL) and dried (MgSO₄). The residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63□m, 60 Å, 40 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl{(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate,which was further purified by preparative HPLC [(reverse phaseX-Bridge-C18, 250×19×5 μm, Flow rate: 19 mL per min, gradient 50% to100% (over 16 min) then 50% (2 min) 0.1% NH₃ in MeCN/water,Wavelength-202 nm] to give ethyl{(3S)-1-[cis-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate,Example 1-15 isomer 1 (104 mg, 36.7%) as a colourless solid and ethyl{(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate,Example 1-15 isomer 2 (37 mg, 13.0%) as a colourless gum.

The data for Example 1-15 isomer 1 and isomer 2 are in Table 3 below.

The absolute stereochemistry of isomer 1 was determined by smallmolecule x-ray crystallography. Isomers can also be separated bypreparative TLC.

Route C

Typical procedure for the preparation of substituted cyclohexylderivatives via Intermediate 13 and Intermediate 20 as exemplified bythe preparation of Example 1-3, ethyl{(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate

1-(3-Fluorophenyl)-4-oxocyclohexanecarbonitrile (200 mg, 0.92 mmol) andethyl (3S)-pyrrolidin-3-ylcarbamate hydrochloride (160 mg, 1.01 mmol)were dissolved in MeOH (6.5 mL) and triethylamine (0.64 mL, 4.60 mmol)were added at rt under N₂. ZnCl₂ (6.2 mg, 0.046 mmol) was added and thereaction mixture was heated at 55° C. for 1 h. The reaction mixture wascooled to 0° C. and sodium cyanoborohydride (289 mg, 4.60 mmol) wasadded in three portions. The reaction mixture was then warmed to rt andstirred for at rt for 14 h. The reaction mixture was partitioned betweenH₂O (100 mL) and EtOAc (100 mL), the aqueous layer was further extractedwith EtOAc (2×100 mL) and the organic layers were combined and dried(Na₂SO₄). Solvent was removed in vacuo and the residue was purified bypreparative TLC to give (ethyl{(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate,Example 1-3 isomer 1 (95 mg, 28.8%) as a colourless gum and ethyl{(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate, Example 1-3 isomer 2 (55 mg, 16.6%) asa colourless gum.

The data for Example 1-3 isomer 2 are in Table 3.

Route D

Typical procedure for the preparation of cyclohexanes via Intermediate31 and Intermediate 12 as exemplified by the preparation of Example3-28, methyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate

4-Oxo-1-phenyl cyclohexanecarbonitrile (10.0 g, 50.2 mmol), tert-butyl1,4-diazepane-1-carboxylate (12.0 g, 60.3 mmol), and AcOH (3.44 mL, 60.2mmol) were dissolved in DCE (100 mL) and heated at 80° C. for 2 h. STAB(16.0 g, 75.4 mmol) was added portionwise and the reaction mixtureheated at reflux for 16 h. The reaction mixture was cooled to rt andpartitioned between H₂O (100 mL) and DCM (100 mL). The aqueous layer wasfurther extracted with DCM (2×50 mL) and the organic extracts werecombined and dried (Na₂SO₄). The solvent was removed in vacuo to givetert-butyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate(5.50 g, 28.6%) as a yellow gum.

Mass: (ESI +ve): 384 (M+H)⁺

tert-Butyl 4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate(5.50 g, 14.3 mmol) was dissolved in 1,4-dioxane (50 mL) and HCl in1,4-dioxane (50 mL, 1.0M) was added. The reaction mixture was stirred atrt for 2 h. The solvent was removed in vacuo, and the residue waspurified by triturating with diethyl ether (2×10 mL) to give4-(1,4-diazepan-1-yl)-1-phenylcyclohexanecarbonitrile hydrochloride(1.18 g, 25.7%) as a white solid.

Mass: (ESI +ve): 284 (M+H)⁺

4-(1,4-Diazepan-1-yl)-1-phenylcyclohexanecarbonitrile hydrochloride(0.50 g, 1.56 mmol) and NEt₃ (0.3 mL, 2.12 mmol) were dissolved in DCM(5.0 mL) and cooled to 0° C. A solution of methylchloroformate (0.17 g,2.12 mmol) in DCM (5.0 mL) was added and the reaction was stirred at rtfor 1h. The solvent was removed in vacuo, and the residue was purifiedby column chromatography (normal phase, silica, 60-120 mesh, gradient 0%to 5% MeOH in DCM) to give methyl4-(4-cyano-4-phenylcyclohexyl)-1,4-diazepane-1-carboxylate, Example 3-28(0.035 g, 6.6%) as a pale yellow gum.

The data for Example 3-28 are in Table 3 below.

Route E

Typical procedure for the preparation of cyclohexanes via Intermediate31 and Intermediate 44 as exemplified by the preparation of Example3-31, prop-2-yn-1-yl4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate

1-(5-Methoxypyridin-2-yl)-4-oxocyclohexanecarbonitrile (632 mg, 2.75mmol), tert-butyl *1,4-diazepane-1-carboxylate (500 mg, 2.50 mmol),ZnCl₂ (102 mg, 0.750 mmol) and NEt₃ (1.8 mL, 12.5 mmol) were dissolvedin MeOH (15 mL) and stirred at 50° C. for 1 h. NaBH₃CN (630 mg., 4.50mmol) was added portionwise at 0° C. and the reaction mixture wasstirred at 50° C. for 7 h. The reaction mixture was partitioned betweenH₂O (80 mL) and EtOAc (50 mL), aqueous layer was further extracted withEtOAc (2×50 mL) and the organic layers were combined and dried (Na₂SO₄).The solvent was removed in vacuo to give tert-butyl4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate(800 mg, 77.3%) as a pale yellow solid.

LCMS (Method C): m/z 415 (M+H)⁺ (ES⁺), at 2.59 min.

tert-Butyl4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate(800 mg, 1.93 mmol) was dissolved in 1,4-dioxane (5.0 mL) and HCl in1,4-dioxane (15 mL, 1.0M) was added. The reaction mixture was stirred atrt for 16 h. The solvent was removed in vacuo, and the residue waspurified by triturating with diethyl ether (3×10 mL) to give4-(1,4-diazepan-1-yl)-1-(5-methoxypyridin-2-yl)cyclohexane-carbonitrile(660 mg, 97.6%) as a white solid.

LCMS (Method C): m/z 315 (M+H)⁺ (ES⁺), at 1.98 min.

4-(1,4-Diazepan-1-yl)-1-(5-methoxypyridin-2-yl)cyclohexanecarbonitrile(300 mg, 0.86 mmol), prop-2-yn-1-ol (0.1 mL, 1.55 mmol) and NEt₃ (0.5mL, 3.43 mmol) were dissolved in toluene (5 mL) and stirred at 0° C. for1 h. Triphosgene (306 mg, 1.03 mmol) was added portionwise and thereaction mixture was stirred at 25° C. for 1 h. The solvent was removedin vacuo, and the residue was partitioned between H₂O (50 mL) and EtOAc(30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and theorganic layers were combined and dried (Na₂SO₄). The solvent was removedin vacuo and crude reaction mixture was purified by Prep HPLC [reversephase HPLC (X-Bridge, 250×19 mm, 5 um, 19 mL per min, gradient 35% (over25 min) 0.1% NH₃ in MeCN/water] to give prop-2-yn-1-yl4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate,Example 3-31 isomer 1 (9 mg, 2.6%) as a yellow gum and prop-2-yn-1-yl4-[4-cyano-4-(5-methoxypyridin-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate,Example 3-31 isomer 2 (10 mg, 3.0%) as a yellow gum.

The data for Example 3-31 isomer 1 are in Table 3 below.

Route F

Typical procedure for the preparation of imidazoles via Intermediate 32as exemplified by the preparation of Example 5-1, ethyl4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate

Ethyl 1,4-diazepane-1-carboxylate hydrochloride (2.0 g, 9.66 mmol),ethyl 4-oxocyclohexanecarboxylate (1.80 g, 10.6 mmol), ZnCl₂ (394 mg,2.90 mmol) and NEt₃ (6.9 mL, 48.3 mmol) were dissolved in MeOH (20 mL)and stirred at 50° C. for 1 h. The reaction mixture was cooled to 0° C.and NaBH₃CN (2.43 g., 38.6 mmol) was added portionwise. The reactionmixture was stirred at 50° C. for 7 h and then the solvents were removedin vacuo, and the residue was partitioned between H₂O (100 mL) and EtOAc(50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and theorganic layers were combined and dried (Na₂SO₄). The solvents wereremoved in vacuo and the residue was purified by column chromatography(normal silica, mesh size: 60-120, 0% to 1.5% MeOH in DCM) to give ethyl4-[4-(ethoxycarbonyl)-cyclohexyl]-1,4-diazepane-1-carboxylate (1.80 g,58.0%) as a pale yellow gum.

LCMS (Method C): m/z 327 (M+H)⁺ (ES⁺), at 2.66 min.

Ethyl 4-[4-(ethoxycarbonyl)cyclohexyl]-1,4-diazepane-1-carboxylate (1.0g, 3.07 mmol), LiOH (211 mg, 9.20 mmol) and H₂O (10 mL) were dissolvedin THF (10 mL) The reaction mixture was stirred at 80° C. for 16 h. Thesolvents were removed in vacuo, and the residue was purified bytituration with diethyl ether (3×10 mL) to give4-[4-(ethoxycarbonyl)-1,4-diazepan-1-yl]cyclohexanecarboxylic acidlithium salt (750 mg, 82.0%) as a white solid.

LCMS (Method C): m/z 299 (M+H)⁺ (ES⁺), at 1.90 min.

4-[4-(Ethoxycarbonyl)-1,4-diazepan-1-yl]cyclohexanecarboxylic acidlithium salt (400 mg, 1.34 mmol), HATU (611 mg, 1.61 mmol), DIPEA (0.7mL, 4.02 mmol) and N,O-dimethylhydroxylaminehydrochloride (156 mg, 1.61mmol) were dissolved in acetonitrile (10.0 mL). The reaction mixture wasstirred at 25° C. for 4 hrs and solvent was removed in vacuo, theresidue was partitioned between H₂O (50 mL) and EtOAc (30 mL), aqueouslayer extracted with EtOAc (2×30 mL), organic layers were combined anddried (Na₂SO₄). The solvents were removed in vacuo and the residue waspurified by column chromatography (normal silica, mesh size: 60-120, 0%to 1.5% Methanol in DCM) to give ethyl4-{4-[methoxy(methyl)carbamoyl]cyclohexyl}-1,4-diazepane-1-carboxylate(300 mg, 66.0%) as a yellow gum.

LCMS (Method C): m/z 342 (M+H)⁺ (ES⁺), at 2.31 min.

Ethyl4-{4-[methoxy(methyl)carbamoyl]cyclohexyl}-1,4-diazepane-1-carboxylate(200 mg, 0.590 mmol) was dissolved in THF (5 mL) and cooled to 0° C. for15 min, LiAlH₄ (1.2 mL, 1.2 mmol, 1.0M sol. in THF) was added slowly andthe reaction mixture was stirred at 10° C. for 1 h. The reaction wasthen quenched with a saturated solution of Na₂SO₄ (15 mL) diluted withH₂O (30 mL), extracted with EtOAc (2×20 mL), and the organic layers werecombined and dried (Na₂SO₄). The solvents were removed in vacuo, toethyl 4-(4-formylcyclohexyl)-1,4-diazepane-1-carboxylate (110 mg, 66.0%)as a pale yellow gum.

LCMS (Method C): m/z 283 (M+H)⁺ (ES⁺), at 2.24 min.

Ethyl 4-(4-formylcyclohexyl)-1,4-diazepane-1-carboxylate (100 mg, 0.354mmol) and pentane-2, 3-dione (42 mg, 0.425 mmol) were dissolved in MeOH(2 mL) and 7 M methanolic ammonia (10 mL) was added. The reactionmixture was degassed with nitrogen and heated at 50° C. for 1 h. Thesolvents were removed in vacuo and the residue was purified by Prep HPLC[reverse phase HPLC (UPLC BEH-C18, 50×2.1 mm, 1.7 um, 0.4 mL per min,gradient 10% to 90% (over 3 min), 100% (1 min) then 10% (over 1 min),0.1% NH₃ in MeCN/water] to give ethyl4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate,Example 5-1 isomer 1 (8 mg, 6.2%) as a colourless gum and ethyl4-[4-(4-ethyl-5-methyl-1H-imidazol-2-yl)cyclohexyl]-1,4-diazepane-1-carboxylate,Example 5-1 isomer 2 (10 mg, 8.0%) as a colourless gum.

The data for Example 5-1 isomer 2 are in Table 3 below

Route G

Typical procedure for the preparation of pyrrolidines via sodiumcyanoborohydride mediated reductive amination, exemplified by Example2-19, ethyl[(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamateIsomer 2

To a solution of5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridine]-2′,4(1′H)-dione(343 mg, 1.4 mmol) and ethyl (S)-pyrrolidin-3-yl-carbamate hydrochloride(270 mg, 1.4 mmol) in MeOH (5 mL), catalytic acetic acid was added andthe mixture stirred at rt for 1 h. After cooling to 0° C., NaCNBH₃ (262mg, 4.2 mmol) was added portionwise and stirred at rt for 4 h. Thesolvent was removed in vacuo before addition of water (20 mL) and DCM(3×30 mL) and the layers separated. Combined organics were washed withbrine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by prep-HPLC (reverse phase, X BRIDGE SHIELD, 19×250 mm, 5p,gradient 10% to 95% MeCN in water containing 0.1% NH₄OH, 210 nm to yieldethyl[(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate,Example 2-19 isomer 1 (77 mg, 14%) as a white solid and ethyl[(3S)-1-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[2,3-c]pyridin]-4-yl)pyrrolidin-3-yl]carbamate,Example 2-19 isomer 2 (38 mg, 7%) as a white solid.

The data for Example 2-19 isomer 1 are in Table 3 below.

Route H Typical procedure for the preparation of ethyl carbamates,exemplified by the preparation of Example 7-2, ethyl{[1-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)piperidin-4-yl]methyl}carbamate

To a solution of4-(4-(aminomethyl)piperidin-1-yl)spiro[cyclohexane-1,3′-indolin]-2′-onedi-TFA salt (200 mg, 0.37 mmol), Et₃N (207 mg, 2.05 mmol) in DCM (10 mL)at 0° C. was added ethyl chloroformate (103 mg, 0.95 mmol) and thereaction mixture stirred at rt for 1 h. The mixture was partitionedbetween cold H₂O (25 mL) and EtOAc (3×15 mL), combined organics dried(Na₂SO₄) and the solvent removed in vacuo. The crude compound waspurified by Prep HPLC (X-bridge-C18, 150×30 mm, 19 mL per min, gradient38% to 62% (over 13 min) then 100% (2 min) 0.1% NH₃ in MeCN/water] togive ethyl((1-(2′-oxospiro[cyclohexane-1,3′-indolin]-4-yl)piperidin-4-yl)methyl)carbamateExample 7-2 isomer 1 (21 mg, 15%) as a colourless gum and ethyl((1-(2′-oxospiro[cyclohexane-1,3′-indolin]-4-yl)piperidin-4-yl)methyl)carbamateExample 7-2 isomer 2 (4 mg, 3%) as a colourless gum.

The data for Example 7-2 isomer 1 and isomer 2 are in Table 3 below.

Route I

Typical procedure for the preparation of 1,4-diazepanes, exemplified bythe preparation of Example 4-17, ethyl4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate

To a solution of5′-methoxyspiro[cyclohexane-1,3′-pyrrolo[2,3-b]pyridine]-2′,4(1′H)-dione(230 mg, 0.93 mmol) in DCM (10 mL), ethyl 1,4-diazepane-1-carboxylate(160 mg, 0.93 mmol) and activated 4 Å molecular sieves were added andstirred at rt for 16 h. After concentration in vacuo the residue wasdissolved in methanol (10 mL) and cooled to 0° C. To the reactionmixture NaCNBH₃ (175 mg, 2.78 mmol) and acetic acid (cat.) were addedand stirred at rt for 16 h. After removing the volatiles, water (20 mL)was added to the reaction mixture and extracted with DCM (3×30 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by prep-HPLC (reversephase, X BRIDGE C-18, 19×250 mm, 5μ, gradient 20% to 95% MeCN in H₂Ocontaining 0.1% NH₄OH, 210 nm) to yield ethyl4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate,Example 4-17 isomer 1 (19 mg, 5%) and ethyl4-(5′-methoxy-2′-oxo-1′,2′-dihydrospiro-[cyclohexane-1,3′-pyrrolo[2,3-b]pyridin]-4-yl)-1,4-diazepane-1-carboxylate,Example 4-17 isomer 2 (38 mg, 10%) both as white solids.

The data for Example 4-17 isomer 1 and isomer 2 are in Table 3 below.

Route J

Preparation of oxindoles via sodium triacetoxyborohydride and titaniumisopropoxide reductive amination, exemplified by the preparation ofExample 10-1, ethyl6-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate

To ethyl 2,6-diazaspiro[3.4]octane-2-carboxylate trifluoroacetic acidsalt (assumed 0.52 mmol) in MeOH was added K₂CO₃ (0.52 mmol) as asolution in H₂O (0.5 mL). The solvent was removed in vacuo andazeotroped with toluene (3×5 mL). The residue was diluted with DCM (10mL) and the mixture treated with4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (112 mg, 0.52 mmol)and Ti(O^(i)Pr)₄ (148 mg, 0.52 mmol). The mixture was stirred at rt for2 h before addition of STAB (220 mg, 1.04 mmol) and glacial acetic acid(7 drops) and further stirring at rt for 16 h. To the mixture was addedsat. aq. NaHCO₃ (10 mL) and the layers separated. The aqueous layer wasfurther washed with DCM and combined organics washed with brine anddried through a Biotage Phase Separator cartridge. The solvent wasremoved in vacuo and the crude residue purified using a 10 g SNAPcartridge and eluting with 0-7%

MeOH in DCM to yield ethyl6-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate,Example 10-1 (10 mg, 5%).

The data for Example 10-1 mixture of isomers are in Table 3 below.

Route K

Procedure for preparation of oxindoles via reductive amination withsodium triacetoxyborohydride, exemplified by the preparation of Example12-1, ethyl8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

To a solution of ethyl 2,8-diazaspiro[4.5]decane-2-carboxylate (203 mg,0.94 mmol) and 4H-spiro[cyclohexane-1,3′-indole]-2′,4(1′H)-dione (200mg, 0.94 mmol) in DCM (5 mL) at rt was added AcOH (5 drops) and themixture stirred for 4 h. STAB (797 mg, 3.76 mmol) was then added and themixture stirred at rt for 16 h. To the mixture was added NaOH (20 mL)and the aqueous layer extracted with DCM (4×25 mL).

Combined organics were dried and the solvent removed in vacuo. Theresidue was loaded onto a 25 g SNAP chromatography cartridge and elutedwith 0-10% MeOH in DCM to yield ethyl8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate,Example 12-1 isomer 1 (3 mg, 1%) and ethyl8-(2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate,Example 12-1 isomer 2 (18 mg, 5%).

The data for Example 12-1 isomer 1 and isomer 2 are in Table 3 below.

Route L

Procedure for preparation of amines via reductive amination with sodiumtriacetoxyborohydride in DMF, exemplified by the preparation of Example19-1,4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile

(1R,3S)-3-(3-Methyl-1,2,4-oxadiazol-5-yl)cyclopentanamine hydrochloridesalt (41 mg, 0.20 mmol) and4-oxo-1-(pyridin-2-yl)cyclohexanecarbonitrile (40 mg, 0.20 mmol) weredissolved in DMF (0.66 mL) and treated with DIPEA (0.04 mL, 0.24 mmol),AcOH (0.08 mL, 1.4 mmol) and STAB (85 mg, 0.40 mmol) in that order. Theresulting mixture was stirred under an atmosphere of nitrogen overnight.Water (10 mL) was added and the mixture was concentrated. The residuewas partitioned between sat. aq. NaHCO₃ (containing some Na₂CO₃) andDCM. The phases were separated and the aqueous phase was extractedfurther with DCM (×2). The combined organic phases were passed through aphase separator cartridge and concentrated to give4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrileas a mixture of diastereomers (73 mg, >100%). The isomers were separatedusing preparative HPLC (Method A, 30-60% gradient) to afford4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile,Example 19-1 Isomer 1 (39 mg, 55%) and4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile,Example 19-1 Isomer 2 (18 mg, 25%).

The data for Example 19-1 Isomer 2 are in Table 3 below.

TABLE 2 Intermediates Table 2 Intermediate Synthetic lntermediatesnumber Name method used Data 1 tert-Butyl methyl(piperidin- — —Commercially available, 4-yl)carbamate CAS: 108612-54-0 2 tert-Butyl(piperidin-4- — — Commercially available, ylmethyl)carbamate CAS:135632-53-0 3 Ethyl 1,5-diazocane-1- 1 55 and 59 LCMS (Method A): m/zcarboxylate 187 (M + H)⁺ (ES+), at trifluoroacetate salt 1.02 min, UVinactive 4 tert-Butyl 2,6- — — Commercially available,diazaspiro[3.4]octane-6- CAS: 885270-86-0 carboxylate 5 tert-Butyl 2,7-— — Commercially available, diazaspiro[3.5]nonane-2- CAS: 236406-55-6carboxylate 6 Ethyl 2,8- 20 53 and 55 LCMS (Method C): m/zdiazaspiro[4.5]decane-2- 213 (M + H)⁺ (ES+), at carboxylate 1.06 min, UVinactive 7 Ethyl 3,7- 1 55 and 60 LCMS (Method A): m/zdiazabicycl[4.2.0]octane- 185 (M + H)⁺ (ES+), at 3-carboxylate 0.95 min,UV inactive trifluoroacetate salt 8 Ethyl hexahydropyrrolo[3,4- 1 55 and61 LCMS (Method A): m/z b]pyrrole-1(2H)- 185 (M + H)⁺ (ES+), atcarboxylate 0.96 min, UV inactive trifluoroacetate salt 9 tert-Butyl — —Commercially available, hexahydropyrrolo[3,4- CAS: 180975-51-3b]pyrrole-5(1H)- carboxylate 10 tert-Butyl 3,7- — — Commerciallyavailable, diazabicyclo[4.2.0]octane- CAS: 885271-73-8 7-carboxylate 11Ethyl (4aS,7aS)- 1 55 and 62 LCMS (Method A): m/zoctahydro-6H-pyrrolo[3,4- 199 (M + H)⁺ (ES+), atb]pyridine-6-carboxylate 1.10 min, UV inactive trifluoroacetate salt 124-Oxo-1- — — Commercially available, phenylcyclohexanecarbonitrile CAS:25115-74-6 13 Ethyl (3S)-pyrrolidin-3- 2 54 and 55 (LCMS Method G) m/zylcarbamate hydrochloride 159 (M + H)⁺ (ES+) 5.32 min, UV active 14Ethyl (3R)-pyrrolidin-3- 2 55 and 63 (LCMS Method Q) m/z ylcarbamatehydrochloride 159 (M + H) (ESI at 2.01 min, UV active 15 tert-Butyl(3S)-pyrrolidin-3- — — Commercially available, ylcarbamate CAS:147081-44-5 16 tert-Butyl (3R)-pyrrolidin-3- — — Commercially available,ylcarbamate CAS: 147081-49-0 17 tert-Butyl methyl[(3S)- —   Commerciallyavailable, pyrrolidin-3-yl]carbamate CAS: 169750-01-0 18 tert-Butylmethyl[(3R)- — — Commercially available, pyrrolidin-3-yl]carbamate CAS:392338-15-7 19 1-(2-Fluorophenyl)-4- 3 — Mass: (ESI + ve): 218oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d6) δ:2.35-2.45 (m, 4 H), 2.53-2.58 (m, 2 H), 2.69-2.78 (m, 2 H), 7.29-7.39(m, 2 H), 7.47-7.54 (m, 2 H). 20 1-(3-Fluorophenyl)-4- 3 — Mass: (ESI +ve): 218 oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.38-2.47 (m, 6 H), 2.66-2.74 (m, 2 H), 7.22-7.27 (m, 1 H), 7.45-7.55(m, 3 H). 21 1-(4-Fluorophenyl)-4- — — Commercially available,oxocyclohexanecarbonitrile CAS: 56326-98-8 22 1-(2-Methylphenyl)-4- 3 —Mass: (ESI + ve): 214 oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR(400MHz, DMSO-d₆) δ: 2.29-2.45 (m, 4 H), 2.54-2.58 (m, 2 H), 2.62 (s, 3H) 2.70- 2.79 (m, 2 H), 7.25-7.32 (m, 3 H), 7.37-7.39 (d, J = 7.2 Hz, 1H). 23 1-(3-Methylphenyl)-4- 3 — Mass: (ESI + ve): 214oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.35-2.48 (m, 9 H), 2.65-2.74 (m, 2 H), 7.20 (d, J = 7.2 Hz, 1 H),7.32-7.43 (m, 3 H). 24 1-(3-Chlorophenyl)-4- 3 — Mass: (ESI +ve): 234oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.37-2.48 (m, 6 H), 2.64-2.74 (m, 2 H), 7.46-7.53 (m, 2 H), 7.59-7.62(m, 1 H), 7.67-7.68 (m, 1 H). 25 1-(3-Methoxyphenyl)-4- 3 — Mass: (ESI +ve): 230 oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.34-2.47 (m, 6 H), 2.65-2.74 (m, 2 H), 3.79 (s, 3 H), 6.95- 6.98 (m, 1H), 7.13 (t, J = 2.4 Hz, 1 H), 7.17-7.20 (m, 1 H), 7.38 (t, J = 8.0 Hz,1 H). 26 4-Oxo-1-(pyridin-2- 4 — Mass: (ESI + ve): 201yl)cyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.35-2.48 (m, 6 H), 2.60-2.74 (m, 2 H), 7.39-7.46 (m, 1 H), 7.65-7.73(m, 1 H), 7.91-7.99 (m, 1 H), 8.60- 8.65 (m, 1 H). 271-(5-Fluoropyridin-2-yl)-4- 4 — Mass: (ESI + ve): 219oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.35-2.50 (m, 6 H), 2.64-2.69 (m, 2 H), 7.79 (m, 1 H), 7.89 (m, 1 H),8.65 (d, J = 2.8 Hz, 1 H). 28 1-(5-Chloropyridin-2-yl)-4- 4 — Mass:(ESI + ve): 235 oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz,DMSO-d₆) δ: 1.90-2.29 1 H), 8.02-8.06 (m, 1 H), 8.68 (d, J = 2.4 Hz, 1H). 29 1-(4-Methylpyridin-2-yl)-4- 4   Mass: (ESI + ve):215oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.11-2.31 (m, 6 H), 2.33 (s, 3 H), 2.50-2.57 (m, 2 H), 7.24 (m, 1 H),7.53 (s, 1 H), 8.44 (m, 1 H). 30 1-(6-Methylpyridin-2-yl)-4- 4 — LCMS(Method A): m/z oxocyclohexanecarbonitrile 215 (M + H)⁺ (ES⁺), at 1.26min, 95%. ¹H NMR (400MHz, DMSO-d₆) δ: 2.38-2.46 (m, 6 H), 2.49 (s, 3 H),2.62-2.70 (m, 2 H), 7.96 (d, J = 8, 1 H), 8.04 (d, J = 8, 1 H), 7.79 (t,J = 8, 1 H). 31 tert-Butyl 1,4-diazepane-1- — — Commercially available,carboxylate CAS: 112275-50-0 32 Ethyl 1,4-diazepane-1- 2 31 and 55 LCMS(Method C): m/z carboxylate hydrochloride 173 (M + H)⁺ (ES⁺), at 1.53min. ¹H NMR (400MHz, DMSO-d₆) δ: 1.20 (t, J = 7.0 Hz, 3 H), 1.93-1.98(m, 2 H), 3.10-3.17 (m, 4 H), 3.39-3.50 (m, 4 H), 4.06 (q, J = 7.0 Hz, 2H), 9.30 (br. s, 2 H). 33 Ethyl 6-hydroxy-1,4- 2 51 and 55 LCMS (MethodC): m/z diazepane-1-carboxylate 189 (M + H)⁺ (ES⁺), at hydrochloride3.33 min. ¹H NMR (400MHz, DMSO-d₆) δ: 1.20 (t, J = 7.2 Hz, 3 H),3.09-3.24 (m, 4 H), 3.36-3.67 (m, 5 H), 4.06 (q, J = 7.2 Hz, 2 H), 5.80(br. s, 1 H), 8.48 (br. s, 1 H), 9.05 (br. s, 1 H). 34 Ethyl6-fluoro-1,4- 2 52 and 55 LCMS (Method A): m/z diazepane-1-carboxylate191 (M + H)⁺ (ES⁺), at hydrochloride 0.91 min. ¹H NMR (400MHz, DMSO-d₆)δ: 1.21-1.27 (m, 3 H), 3.38-3.80 (m, 8 H), 4.05-4.10 (m, 2 H), 5.14 (d,J = 43.2, 1 H), 8.85 (br. s, 1 H), 9.48 (br. s, 1 H). 351-(2-Chlorophenyl)-4- — — Commercially available,oxocyclohexanecarbonitrile CAS: 65618-88-4 36 1-(4-Chlorophenyl)-4- — —Commercially available, oxocyclohexanecarbonitrile CAS: 25115-75-7 371-(4-Methoxyphenyl)-4- — — Commercially available,oxocyclohexanecarbonitrile CAS: 5309-14-8 38 4-Oxo-1-[2- — —Commercially available, (trifluoromethyl)phenyl] CAS: 943326-34-9cyclohexanecarbonitrile 40 4-Oxo-1-(pyridin-4- 4 — Mass: (ESI + ve): 201yl)cyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.17-2.26 (m, 4 H), 2.35-2.39 (m, 4 H), 7.91-7.93 (m, 2 H), 8.52-8.53(m, 2 H). 41 1-(3-Chloropyridin-2-yl)-4- 4 — Mass: (ESI + ve): 235oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, DMSO-d₆) δ:2.41-2.44 (m, 2 H), 2.54-2.55 (m, 2 H), 2.64-2.71 (m, 4 H), 7.53-7.53(m, 1 H), 8.08-8.11 (m, 1 H), 8.60- 8.62 (m, 1 H). 421-(5-Bromopyridin-2-yl)-4- 4 — LCMS (Method A): m/zoxocyclohexanecarbonitrile 280/282 (M + H)⁺ (ES⁺), at 1.49 min. ¹H NMR(400MHz, CDCl₃) 6: 2.39-2.61 (m, 6 H), 2.81-2.93 (m, 2 H), 7.60-7.64 (m,1 H), 7.91-7.95 (m, 1 H), 8.60- 8.62 (m, 1 H). 431-(5-Methylpyridin-2-yl)-4- 4 — Mass: (ESI + ve): 215oxocyclohexanecarbonitrile (M + H)⁺ ¹H NMR (400MHz, CDCl₃) δ: 2.29-2.34(m, 4 H), 2.58-2.60 (m, 4 H), 2.61 (s, 3 H), 7.78- 7.84 (m, 1 H),7.91-7.99 (m, 1 H), 8.84-8.89 (m, 1 H). 44 1-(5-Methoxypyridin-2-yl)-4-4 — LCMS (Method A): m/z oxocyclohexanecarbonitrile 231 (M + H)⁺ (ES⁺),at 1.15 min. ¹H NMR (400MHz, DMSO-d₆) δ: 2.36-2.44 (m, 4 H), 2.51-2.69(m, 4 H), 3.85 (s, 3 H), 7.49- 7.52 (m, 1 H), 7.62-7.65 (m, 1 H),8.32-8.36 (m, 1 H). 45 1-(5-Ethoxypyridin-2-yl)-4- 4 — LCMS (Method C):m/z oxocyclohexanecarbonitrile 244 (M + H)⁺ (ES⁺), at 3.03 min. ¹H NMR(400MHz, DMSO-d₆) δ: 1.35 (t, J = 6.8 Hz, 3 H), 2.37-2.46 (m, 2 H),2.62-2.67 (m, 2 H), 3.47-3.51 (m, 2 H), 3.65-3.76 (m, 2 H), 4.13 (q, J =6.8 Hz, 2 H), 7.47-7.50 (m, 1 H), 7.59- 7.61 (m, 1 H), 8.32 (s, 1 H). 464-Oxo-1-[5- 4 — Mass: (ESI + ve): 269 (trifluoromethyl)pyridin-2- (M +H)⁺ yl]cyclohexanecarbonitrile ¹H NMR (400MHz, DMSO-d₆) δ: 2.43-2.63 (m,6 H), 2.84-2.90 (m, 2 H), 7.86-7.91 (m, 2 H), 8.05-8.06 (m, 1 H). 474-Oxo-1-[6- 4 — LCMS (Method A): m/z (trifluoromethyl)pyridin-2- 269(M + H)⁺ (ES⁺), at yl]cyclohexanecarbonitrile 1.60 min. ¹H NMR (400MHz,DMSO-d₆) δ: 2.41-2.45 (m, 2 H), 2.50-2.53 (m, 4 H), 2.65-2.73 (m, 2 H),7.96-7.98 (m, 1 H), 8.03-8.06 (m, 1 H), 8.23- 8.27 (m, 1 H). 484-Oxo-1-(thiophen-2- — — Commercially available,yl)cyclohexanecarbonitrile CAS: 65619-58-1 49 Methyl 4-oxo-1- — —Commercially available, phenylcyclohexanecarboxylate CAS: 75945-90-3 50Methyl 1-(3- 5   Mass: (ESI + ve): 268 chloropyridin-2-yl)-4- (M + H)⁺oxocyclohexanecarboxylate ¹H NMR (400MHz, DMSO-d₆) δ: 2.39-2.49 (m, 6H), 2.52-2.56 (m, 2 H), 3.64 (s, 3 H), 7.39- 7.43 (m, 1 H), 7.93-7.95(m, 1 H), 8.53-8.56 (m, 1 H). 51 tert-Butyl 6-hydroxy-1,4- — —Commercially available, diazepane-1-carboxylate CAS: 956317-40-1 52tert-Butyl-6-fluoro-1,4- — — Commercially available, diazepane-1carboxylate CAS: 1261297-63-5 53 tert-Butyl 2,8- — — Commerciallyavailable, diazaspiro[4.5]decane-8- CAS: 236406-39-6 carboxylate 55Ethyl chloroformate — — Commercially available, CAS: 541-41-3 56 Methylchloroformate — — Commercially available, CAS: 79-22-1 57 Propargylchloroformate — — Commercially available, CAS: 35718-08-2 58 2-Butynylchloroformate — — Commercially available, CAS: 202591-85-3 59 tert-Butyl1,5-diazocane-1- — — Commercially available, carboxylate CAS:223797-64-6 61 tert-Butyl 2,7- — — Commercially available,diazabicyclo[3.3.0]octane- CAS: 132414-81-4 7-carboxylate 62(4AS,7aS)-Octahydro- — — Commercially available,1H-pyrrolo[3,4-b]pyridine-1- CAS: 159991-07-8 carboxylic acid tert-butylester 64 2-Fluoroethyl Commercially available, chloroformate CAS:462-27-1 65 4H-Spiro[cyclohexane- — — Commercially available,1,3′-indole]-2′,4(1′H)-dione CAS: 52140-59-7 66 7-Methyl-1,3-dihydro-2H-— — Commercially available, indol-2-one CAS: 3680-28-2 67 7′-Methyl-4H-6 66 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H)⁺ (ES⁺), atindole]-2′,4(1′H)-dione 1.91 min, UV active. 68 6′-Methyl-4H- 6 69 LCMS(Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H)⁺ (ES⁺), atindole]-2′,4(1′H)-dione 1.90 min, UV active. 69 6-Methyl-1,3-dihydro-2H-— — Commercially available, indol-2-one CAS: 56341-38-9 70 5′-Methyl-4H-6 71 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H)⁺ (ES⁺), atindole]-2′,4(1′H)-dione — — 1.87 min, UV active. 715-Methyl-1,3-dihydro-2H- Commercially available, indol-2-one CAS:3484-35-3 72 4′-Methyl-4H- 6 73 LCMS (Method F): m/zspiro[cyclohexane-1,3′- 230 (M + H)⁺ (ES⁺), at indole]-2′,4(1′H)-dione1.86 min, UV active. 73 4-Methyl-1,3-dihydro-2H- — — Commerciallyavailable, indol-2-one CAS: 13220-46-7 74 6′-Fluoro-4H- 6 75 LCMS(Method F): m/z spiro[cyclohexane-1,3′- 234 (M + H)⁺ (ES⁺), atindole]-2′,4(1′H)-dione 1.83 min, UV active. 75 6-Fluoro-1,3-dihydro-2H-— — Commercially available, indol-2-one CAS: 56341-39-0 76 5′-Fluoro-4H-6 77 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 234 (M + H)⁺ (ES⁺), atindole]-2′,4(1′H)-dione 1.81 min, UV active. 77 5-Fluoro-1,3-dihydro-2H-— — Commercially available, indol-2-one CAS: 56341-41-4 786′-Methoxy-4H- 6 79 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 244[M-H]⁻ (ES⁻), at 1.83 indole]-2′,4(1′H)-dione min, UV active. 796-Methoxy-1,3-dihydro-2H- — — Commercially available, indol-2-one CAS:7699-19-6 80 5′-Methoxy-4H- 6 81 LCMS (Method F): m/zspiro[cyclohexane-1,3′- 246 (M + H)⁺ (ES⁻), at 1.81indole]-2′,4(1′H)-dione min, UV active. 81 5-Methoxy-1,3-dihydro-2H- — —Commercially available, indol-2-one CAS: 7699-18-5 82 Ethyl methyl[(3S)-1 55 and 83 LCMS (Method F): m/z pyrrolidin-3-yl]carbamate 173 (M + H)⁺(ES⁺), at trifluoroacetic acid salt 0.95 min, UV active. 83 tert-Butyl(3S)-3-(methylamino) — — Commercially available,pyrrolidine-1-carboxylate CAS: 147081-59-2 84 Ethyl methyl[(3R)- 7 16,LCMS (Method F): m/z pyrrolidin-3-yl]carbamate 55 and 85 173 (M + H)⁺(ES⁺), at trifluoroacetic acid salt 0.95 min, UV active. 85 Methyliodide — — Commercially available, CAS: 74-88-4 86 1′-Methyl-4H- 8 65and 85 LCMS (Method F): m/z spiro[cyclohexane-1,3′- 230 (M + H)⁺ (ES⁺),at indole]-2′,4(1′H)-dione 1.91 min, UV active. 87 Ethyl 2′,4-dioxospiro9 55 and 65 LCMS (Method F): m/z [cyclohexane-1,3′-indole]- 288 (M + H)⁺(ES⁺), at 1′(2′H)-carboxylate 2.18 min, UV active. 88 2-(2′,4-Dioxospiro8 65 and 89 LCMS (Method F): m/z [cyclohexane-1,3′-indol]- 273 (M + H)⁺(ES⁺), at 1′(2′H)-yl)acetamide 1.69 min, UV active. 89 2-Chloroacetamide— — Commercially available, CAS: 79-07-2 90 4H-Spiro[cyclohexane- 10 91and 92 LCMS (Method F): m/z 1,3′-pyrrolo[2,3-b]pyridine]- 217 (M + H)⁺(ES⁺), at 2′,4(1′H)-dione 1.51 min, UV active. 913-Fluoro-2-nitropyridine — — Commercially available, CAS: 54231-35-5 92(Buta-1,3-dien-2- — — Commercially available, yloxy)(trimethyl)silaneCAS: 38053-91-7 93 5′-Chloro-4H-spiro 11 94 LCMS (Method F): m/z[cyclohexane-1,3′-pyrrolo[2,3-b] 251 (M + H)⁺ (ES⁺), atpyridine]-2′,4(1′H)-dione 1.73 min, UV active. 945-Chloro-1,3-dihydro-2H- — — Commercially available,pyrrolo[2,3-b]pyridin-2-one CAS: 1190314-60-3 95 5′-Methoxy-4H- 12 92and 96 LCMS (Method L): m/z spiro[cyclohexane-1,3′- 247 (M + H)⁺ (ES⁺),at 3.64 pyrrolo[2,3-c]pyridine]- min, UV active. 2′,4(1′H)-dione 962,4-Dichloro-5- — — Commercially available, nitropyridine CAS: 4487-56-397 5′-Methoxy-4H- LCMS (Method F): m/z spiro[cyclohexane-1,3′- 13 92 and98 247 (M + H)⁺ (ES⁺), at 1.93 pyrrolo[3,2-b]pyridine]- min, UV active2′,4(1′H)-dione 98 2-Chloro-6-methoxy-3- — — Commercially available,nitropyridine CAS: 38533-61-8 99 4H-Spiro[cyclohexane- 16 92 and 100LCMS (Method E): m/z 1,3′-pyrrolo[3,2-b]pyridine]- 217 (M + H)⁺ (ES⁺),at 1.62 2′,4(1′H)-dione min, UV active 100 2-Chloro-3-nitropyridine — —Commercially available, CAS: 5470-18-8 101 Ethyl piperidin-4- 1 55 and102 LCMS (Method F): m/z ylcarbamate trifluoroacetic 173 (M + H)⁺ (ES⁺),at 3.97 acid salt min, UV active 102 tert-Butyl 4-aminopiperidine-1- — —Commercially available, carboxylate CAS: 87120-72-7 1034-[4-(Aminomethyl) 14 2 and 65 LCMS (Method F): m/z piperidin-1-yl]spiro314 (M + H)⁺ (ES⁺), at 0.76 [cyclohexane-1,3′- min (isomer 1) and 1.47indol ]-2′(1′H)-one di- (isomer 2), UV active trifluoroacetic acid salt,mixture of two isomers 104 Methyl 1,4-diazepane-1- 2 31 and 56 LCMS(Method H): m/z carboxylate hydrochloride 159 (M + H)⁺ (ES⁺), at 5.25min, UV active 105 1-(1,4-Diazepan-1- 2 31 and 106 LCMS (Method Q): m/zyl)butan-1-one 171 (M + H)⁺ (ES⁺), at 2.92 hydrochloride min, UV active106 Butyryl chloride — — Commercially available, CAS: 141-75-3 1071-(1,4-Diazepan-1-yl)but- 15 31 and 108 LCMS (Method H): m/z 2-en-1-onetrifluoroacetic 169 (M + H)⁺ (ES⁺), at 5.28 acid salt min, UV active 108Crotonyl chloride — — Commercially available, CAS: 625-35-4 1092-Oxo-2,3-dihydro-1 H- — — Commercially available, indole-6-carbonitrileCAS: 199327-63-4 110 2′,4-Dioxo-1′,2′- 6 109 LCMS (Method F): m/zdihydrospiro[cyclohexane- 239 (M-H)⁻ (ES⁻), at 1.72 1,3′-indole]-6′-carbonitrile min, UV active 111 2-Oxo-2,3-dihydro-1H- — —Commercially available, indole-5-carbonitrile CAS: 61394-50-1 1122′,4-Dioxo-1′,2′- 6 111 Mass: (ESI-ve):: 239 (M-dihydrospiro[cyclohexane- H)⁻ 1,3′-indole]-5′-carbonitrile 1135′-Methoxy-4H- 17 114 Mass: (ESI + ve): 247 spiro[cyclohexane-1,3′- (M +H)⁺ pyrrolo[2,3-b]pyridine]- 2′,4(1′H)-dione 1145-Methoxy-1H-pyrrolo[2,3- — — Commercially available, b]pyridine CAS:183208-36-8 115 (2-Chloropyridin-3- — — Commercially available,yl)acetonitrile CAS: 101012-32-2 116 1′,2′-Dihydro-4H-spiro 18 115 LCMS(Method G): m/z [cyclohexane-1,3′-pyrrolo 203 (M + H)⁺ (ES⁺), at[2,3-b]pyridin]-4-one 4.12 min, UV active 117 1′-(Methylsulfonyl)-1′,2′-19 116 LCMS (Method F): m/z dihydro-4H- 281 (M + H)⁺ (ES⁺), atspiro[cyclohexane-1,3′- 1.73 min, UV active pyrrolo[2,3-b]pyridin]-4-one118 4H-Spiro[cyclohexane- 13 119 LCMS (Method G): m/z1,3′-pyrrolo[2,3-c]pyridine]- 217 (M + H)⁺ (ES⁺), at 2′,4(1′H)-dione3.39 min, UV active 119 4-Chloro-3-nitropyridine — — Commerciallyavailable, CAS: 13091-23-1 120 5′-Methyl-4H-spiro 13 121 LCMS (MethodF): m/z [cyclohexane-1,3′-pyrrolo[3,2- 231 (M +H) +(ES +), atb]pyridine]-2′,4(1′H)-dione 1.67 min, UV active 121 2-Chloro-6-methyl-3-— — Commercially available, nitropyridine CAS: 56057-19-3 122 Ethyl 2,6-1 4 and 55 LCMS (Method K): m/z diazaspiro[3.4]octane-2- 185 (M + H)⁺(ES⁺), at carboxylate trifluoroacetic 3.50 min, UV active acid salt 123(1S,3R)-3- — — Commercially available, Aminocyclopentanecarboxylic CAS:71830-07-4 acid 124 Di-tert-butyl dicarbonate — — Commerciallyavailable, CAS: 24424-99-5 125 N-Hydroxyethanimidamide — — Commerciallyavailable, CAS: 22059-22-9 126 (1R,3S)-3-(3-Methyl-1,2,4- 21 123, LCMS(Method E): m/z oxadiazol-5- 124 and 125 168 (M + H)⁺ (ES⁺), atyl)cyclopentanamine 1.20 min, UV active hydrochloride salt 127N-Hydroxypropanimidamide — — Commercially available, CAS: 29335-36-2 128(1R,3S)-3-(3-Ethyl-1,2,4- 21 123, LCMS (Method E): m/z oxadiazol-5- 124and 127 182 (M + H)⁺ (ES⁺), at yl)cyclopentanamine 1.82 min, UV activehydrochloride salt 129 2-(tert-Butoxycarbonyl)-2- — — Commerciallyavailable, azaspiro[3.3]heptane-6- CAS: 1211526-53-2 carboxylic acid 1302,2,2-Trifluoro-N- — — Commercially available, hydroxyethanimidamideCAS: 4314-35-6 131 6-[3-(Trifluoromethyl)- 22 129 and 130 LCMS (MethodE): m/z 1,2,4-oxadiazol-5-yl]-2- 234 (M + H)⁺ (ES⁺), at azaspiro[3.3]heptane 2.96 min, UV active trifluoroacetic acid salt 1326-tert-Butyl 2-methyl 6- — — Commercially available,azaspiro[3.4]octane-2,6- CAS: 203662-61-7 dicarboxylate 1332-(3-Methyl-1,2,4- 23 132 and 125 LCMS (Method E): m/zoxadiazol-5-yl)-6-azaspiro[3.4] 194 (M + H)⁺ (ES⁺), atoctanehydrochloride salt 1.57 min, UV active 134 Ethyl piperidine-3- — —Commercially available, carboxylate CAS: 5006-62-2 135(3R)-3-(3-Methyl-1,2,4- 24 134 LCMS (Method I): m/zoxadiazol-5-yl)piperidine 124 and 125 168 (M + H)⁺ (ES⁺), at 2.57 min,UV active 136 Methyl 2- — — Commercially available,(aminomethyl)cyclopropan CAS: 1630906-92-1 ecarboxylate hydrochloridesalt 137 1-[2-(3-Methyl-1,2,4- 25 136, LCMS (Method E): m/z oxadiazol-5-124 and 125 154 (M +H) +(ES), at yl)cyclopropyl]methanamine 0.71 min, UVactive hydrochloride salt 138 (1R,3S)-3-[3- 21 123, LCMS (Method E): m/z(Trifluoromethyl)-1,2,4- 124 and 130 222 (M + H)⁺ (ES⁺), at oxadiazol-5-2.71 min, UV active. yl]cyclopentanamine hydrochloride salt 1392-(tert-Butoxycarbonyl)-2- — — Commercially available,azaspiro[3.3]heptane-6- CAS: 1211526-53-2 carboxylic acid 1406-(3-Ethyl-1,2,4-oxadiazol-5- 22 129 and 127 LCMS (Method E): m/zyl)-2-azaspiro[3.3]heptane 194 (M + H)⁺ (ES⁺), at trifluoroacetic acidsalt 2.21 min, UV active. 141 2-(3-Ethyl-1,2,4-oxadiazol- 22 132 and 127LCMS (Method B): m/z 5-yl)-6-azaspiro[3.4]octane 208 (M + H)⁺ (ES⁺), athydrochloride salt 1.83 min, UV active 142 Cyclopropanecarboxylic — —Commercially available, acid, 2-[[[(1,1- CAS: 1000535-88-5dimethylethoxy)carbonyl] amino]methyl]- 1431-[2-(3-Ethyl-1,2,4-oxadiazol-5- 22 142 and 127 LCMS (Method B): m/zyl)cyclopropyl]methanamine 168 (M + H)⁺ (ES⁺), at hydrochloride salt1.33 min, UV active

TABLE 3 Syn- Ex. Inter- thetic LCMS LCMS No. Name mediate method ¹H NMRMethod data  1-1 Isomer 2: ethyl [(3S)-1- 12 c (400 MHz, CDCl₃) δ: 1.26(t, J = 5.6 Hz, 3 H), 1.47-1.52 (m, 1 D m/z 342 (4-cyano-4- and H),1.63-1.65 (m, 1 H), 1.90-1.98 (m, 5 H), 2.28-2.39 (m, 5 (M + H)⁺phenylcyclohexyl)pyrrolidin- 13 H), 2.56-2.82 (m, 3 H), 4.12-4.14 (m, 2H), 4.22-4.28 (m, 1 (ES⁺), at 3-yl]carbamate H), 4.83-4.89 (m, 1 H),7.33 (t, J = 4, 1 H), 7.43 (t, J = 7.2 Hz, 5.87 min, 2 H), 7.39 (d, J =7.6 Hz, 2 H). UV active  1-2 Isomer 2: ethyl [(3R)-1- 12 c (400 MHz,CDCl₃) δ: 1.24 (t, J = 6.6 Hz, 3 H), 1.60-1.65 (m, 1 D m/z 342(4-cyano-4- and H), 1.87-1.97 (m, 6 H), 2.22-2.27 (m, 3 H), 2.34-2.40(m, 2 (M + H)⁺ phenylcyclohexyl)pyrrolidin- 14 H), 2.52-2.56 (m, 1 H),2.65-2.66 (m, 1 H), 2.79-2.80 (m, 1 (ES⁺), at 3-yl]carbamate H),4.08-4.12 (m, 2 H), 4.20-4.18 (m, 1 H), 4.83-4.88 (m, 1 5.85 min, H),7.34 (t, J = 7.2 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.48 UV active (d,J = 7.6 Hz, 2 H).  1-3 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d₆)δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.49-1.65 (m, C m/z 360 [4-cyano-4-(3- and1 H), 1.66-1.82 (m, 2 H), 1.82-2.14 (m, 6 H), 2.15-2.31 (m, 3 (M + H)⁺fluorophenyl)cyclohexyl] 20 H), 2.31-2.42 (m, 1 H), 2.58-2.70 (m, 1 H),2.70-2.85 (m, 1 (ES⁺), at pyrrolidin-3-yl}carbamate H), 3.96 (q, J = 7.2Hz, 3 H), 7.17-7.26 (m, 1 H), 7.29-7.42 (m, 2.97 min, 2H), 7.45-7.55 (m,1 H). N-H not observed. UV active  1-4 Isomer 2: ethyl {(3S)-1- 13 c(400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0 Hz, 3 H), 1.57-1.60 (m, C m/z 360[4-cyano-4-(4- and 1 H), 1.69-1.81 (m, 2 H), 1.85-1.99 (m, 4 H),2.01-2.12 (m, 2 (M + H)⁺ fluorophenyl)cyclohexyl] 21 H), 2.17-2.25 (m, 2H), 2.30-2.42 (m, 2 H), 2.60-2.67 (m, 1 (ES⁺), atpyrrolidin-3-yl}carbamate H), 2.68-2.75 (m, 2 H), 3.96 (q, J = 7.0 Hz, 3H), 7.26-7.33 (m, 2.97 min, 2 H), 7.55-7.58 (m, 2 H). UV active  1-5Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.2 Hz,3 H), 1.54-1.59 (m, C m/z 360 [4-cyano-4-(2- and 1 H), 1.78-1.92 (m, 2H), 1.96-2.05 (m, 5 H), 2.19-2.34 (m, 4 (M + H)⁺fluorophenyl)cyclohexyl] 19 H), 2.42-2.45 (m, 1 H), 2.53-2.58 (m, 1 H),2.71-2.75 (m, 1 H), 2.89 min, pyrrolidin-3-yl}carbamate 3.95 (q, J = 7.2Hz, 3 H), 7.26-7.34 (m, 3 H), 7.43-7.53 (m, 2 H). (ES⁺), at UV active 1-6 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO) δ: 1.14 (t, J = 7.2Hz, 3 H), 1.56-1.61 (m, 1 m/z 360 [4-cyano-4-(3- and H), 1.74-1.78 (m, 2H), 1.87-1.90 (m, 3 H), 2.01-2.08 (m, 1 C (M + H)⁺fluorophenyl)cyclohexyl] 20 H), 2.15-2.51 (m, 6 H), 2.63-2.66 (m, 2 H),3.93-3.98 (m, 3 (ES⁺), at pyrrolidin-3-yl}carbamate H), 7.20-7.25 (m, 1H), 7.35-7.39 (m, 3 H), 7.48-7.54 (m, 1H). 2.97 min, UV active  1-7Isomer 2: ethyl {(3R)-1- 14 c (400 MHz, DMSO-d₆) δ: δ: 1.15 (t, J = 6.8Hz, 3 H), 1.59-1.65 C m/z 360 [4-cyano-4-(4- and (m, 1 H), 1.74-1.80 (m,2H), 1.81-1.96 (m, 4 H), 2.01-2.10 (M + H)⁺ fluorophenyl)cyclohexyl] 21(m, 2H), 2.15-2.55 (m, 4 H), 2.60-2.73 (m, 2 H), 3.93-4.00 (ES⁺), atpyrrolidin-3-yl}carbamate (m, 3 H), 7.22-7.28 (m, 3 H), 7.50-7.61 (m, 2H). 2.93 min, UV active  1-8 Isomer 2: ethyl {(3R)-1- 14 c (400 MHz,DMSO-d₆) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.55-1.60 (m, C m/z 356[4-cyano-4-(2- and 1 H), 1.77-1.83 (m, 2 H), 1.92-2.05 (m, 5 H),2.18-2.20 (m, 2 (M + H)⁺ methylphenyl)cyclohexyl] 22 H), 2.31-2.34(m, 2H), 2.41-2.45 (m, 2 H), 2.57 (s, 3 H), 2.65- (ES⁺), atpyrrolidin-3-yl}carbamate 2.74 (m, 2 H), 3.95 (q, J = 7.2 Hz, 3 H),7.25-7.30 (m, 3 H), 7.40- 3.02 min, 7.42 (t, J = 6.4 Hz, 1 H). UV active 1-9 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d₆) δ: 1.15 (t, J =6.8 Hz, 3 H), 1.48-1.59 (m, C m/z 356 [4-cyano-4-(3- and 3 H), 1.70-2.10(m, 7 H), 2.18-2.39 (m, 2 H), 2.40-2.50 (m, 5 (M + H)⁺methylphenyl)cyclohexyl] 23 H), 2.64-2.87 (m, 2 H), 3.94-4.00 (q, J =7.2 Hz, 3 H), 7.15- (ES⁺), at pyrrolidin-3-yl}carbamate 7.17 (m, 1H),7.27-7.34 (m, 3 H). 2.71 min, C UV active  1-10 Isomer 2: ethyl {(3S)-1-13 c (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 6.8 Hz, 3 H), 1.57-1.60 (m, m/z376 [4-(3-chlorophenyl)-4- and 1 H), 1.71-1.77 (m, 3 H), 1.87-1.89 (m, 4H), 2.03-2.07 (m, 1 (M + H)⁺ cyanocyclohexyl]pyrrolidin- 24 H),2.17-2.32 (m, 3 H), 2.25-2.40 (m, 2 H), 2.59-2.68 (m, 2 (ES⁺), at3-yl}carbamate H), 3.96 (q, J = 6.8 Hz, 3 H), 7.32 (d, J = 7.6 Hz, 1 H),7.44- 3.10 min, 7.54 (m, 3H). UV active  1-11 Isomer 2: ethyl {(3S)-1-13 c (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 6.4 Hz, 3 H), 1.85-1.99 (m, Cm/z 372 [4-cyano-4-(3- and 1 H), 1.74-2.09 (m, 7 H), 2.20-2.41 (m, 5 H),2.61-2.67 (m, 2 (M + H)⁺ methoxyphenyl)cyclohexyl] 25 H), 3.79 (s, 3 H),3.95 (q, J = 6.4 Hz, 3 H), 6.95 (d, J = 8.0 Hz, 1 (ES⁺), atpyrrolidin-3- H), 7.01 (s, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.30-7.39(m, 2 H). 2.67 min, yl}carbamate UV active  1-12 Isomer 2: ethyl{(3S)-1- 13 c (400 MHz, CD30D) δ: 1.23 (t, J = 7.2 Hz, 3 H), 1.70-1.74(m, 1 C m/z 343 [4-cyano-4-(pyridin-2- and H), 1.80-2.05 (m, 7 H),2.17-2.30 (m, 1 H), 2.47-2.55 (m, 1 (M + H)⁺ yl)cyclohexyl]pyrrolidin-3-26 H), 2.57-2.67 (m, 4 H), 2.87-2.93 (m, 2 H), 4.06 (q, J = 7.2 Hz,(ES⁺), at yl}carbamate 2 H), 4.10-4.21 (m, 1 H), 7.39 (dd, J = 7.2 Hz,5.2, 1 H), 7.69 (d, 2.50 min, J = 7.6 Hz, 1 H), 7.91 (t, J = 8.0 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H). UV active  1-13 Isomer 2: ethyl {(3R)-1-14 c (400 MHz, CD₃OD) δ: 1.20 (t, J = 7.2 Hz, 3 H), 1.71-1.76 (m, 1 Cm/z 343 ]4-cyano-4-(pyridin-2- and H), 1.83-2.05 (m, 7 H), 2.17-2.30 (m,1 H), 2.50-2.70 (m, 5 (M + H)⁺ yl)cyclohexyl]pyrrolidin-3- 26 H),2.87-2.95 (m, 2 H), 4.07 (q, J = 7.2 Hz, 2H), 4.11-4.20 (m, (ES⁺), atyl}carbamate 1 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.70 (d, J = 7.2 Hz, 1 H),7.91 (t, 2.52 min, J = 6.8 Hz, 1 H), 8.62 (d, J = 4.8 Hz, 1 H). UVactive  1-14 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d₆) δ: 1.15(t, J = 6.8 Hz, 3 H), 1.56-1.62 (m, C m/z 361 [4-cyano-4-(5- and 1 H),1.66-2.15 (m, 8 H), 2.21-2.45 (m, 4 H), 2.46-2.52 (m, 1 (M + H)⁺fluoropyridin-2- 27 H), 2.70-2.80 (m, 1 H), 3.92-4.01 (m, 3 H), 7.28 (d,J = 7.2 Hz, (ES⁺), at yl)cyclohexyl]pyrrolidin-3- 1 H), 7.68-7.72 (m,1H), 7.82-7.86 (m, 1 H), 8.64-8.66 (m, 1 H). 2.62 min, yl}carbamate UVactive  1-15 Isomer 2: ethyl {(3S)-1- 15, 28 b (400 MHz, DMSO-d₆) δ:1.14 (t, J = 7.0 Hz, 3 H), 1.38-1.66 (m, B m/z 377[trans-4-(5-chloropyridin- and 1 H), 1.66-2.19 (m, 8 H), 2.13-2.37 (m, 4H), 2.40-2.43 (m, 1 (M + H)⁺ 2-yl)-4- 55 H), 2.74 (t, J = 8.0 Hz, 1 H),3.87-3.95 (m, 1 H), 3.96 (q, J = 7.0 (ES⁺), atcyanocyclohexyl]pyrrolidin- Hz, 2 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.66(dd, J = 8.5 Hz, 0.8, 1 3.95 min, 3-yl}carbamate H), 8.04 (dd, J = 8.5Hz, 2.5 Hz, 1 H) and 8.70 (dd, J = 2.5 Hz, UV active 0.8, 1 H).  1-16Isomer 2: ethyl {(3R)-1- 16, 28 b (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0Hz, 3 H), 1.48-1.66 (m, B m/z 377 [4-(5-chloropyridin-2-yl)-4- and 1 H),1.66-2.19 (m, 8 H), 2.24-2.37 (m, 3 H), 2.41-2.49 (m, 1 (M + H)⁺cyanocyclohexyl]pyrrolidin- 55 H), 2.53-2.60 (m, 1 H), 2.75 (t, J = 8.0Hz, 1 H), 3.87-3.95 (m, (ES⁺), at 3-yl}carbamate 1 H), 3.96 (q, J = 7.0Hz, 2 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.66 3.97 min, (dd, J = 8.5, 0.8Hz, 1 H), 8.04 (dd, J = 8.5, 2.5 Hz, 1 H), 8.70 UV active (dd, J = 2.5,0.8 Hz, 1 H)  1-17 Isomer 2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d₆) δ:1.14 (t, J = 7.0 Hz, 3 H), 1.56-1.60 (m, C m/z 357 [4-cyano-4-(4- and 1H), 1.70-1.93 (m, 6 H), 2.00-2.08 (m, 2 H), 2.25-2.37 (m, 4 (M + H)⁺methylpyridin-2- 29 H), 2.38 (s, 3 H), 2.47-2.50 (m, 1 H), 2.74-2.78 (m,1 H), 3.99- (ES⁺), at yl)cyclohexyl]pyrrolidin-3- 3.99 (m, 3 H),7.22-7.23 (m, 1 H), 7.27-7.29 (m,1 H), 7.43 (s, 1 2.66 min, yl}carbamateH), 8.46-8.48 (m, 1 H). UV active  1-18 Isomer 2: ethyl {(3S)-1- 13 c(400 MHz, CDCl₃) δ: 1.28 (t, J = 7.2 Hz, 3 H), 1.80-2.00 (m, 3 C m/z 358[4-cyano-4-(6- and H), 2.19-2.40 (m, 8 H), 2.55 (s, 3 H), 2.64-2.95 (m,2 H), 3.05- (M + H)⁺ methylpyridin-2- 30 3.35 (m, 2 H), 4.12 (q, J = 7.2Hz, 2 H), 4.30-4.45 (m, 1 H), 7.10 (ES⁺), at yl)cyclohexyl]pyrrolidin-3-(d, J = 8 Hz, 1 H), 7.43 (d, J = 8 Hz, 1 H), 7.62 (t, J = 8, 1 H). 2.65min, yl}carbamate N-H not observed. UV active  1-19 Isomer 2: ethyl{(3R)-1- 14 c (400 MHz, DMSO-d₆) δ: 1.14 (t, J = 7.2 Hz, 3 H), 1.56-1.61(m, C m/z 357 [4-cyano-4-(4- and 1 H), 1.70-2.10 (m, 8 H), 2.25-2.37 (m,4 H), 2.38 (s, 3 H), (M + H)⁺ methylpyridin-2- 29 2.45-2.50 (m, 1 H),2.72-2.77 (m, 1 H), 3.93-4.05 (m, 3 H), (ES⁺), atyl)cyclohexyl]pyrrolidin-3- 7.23 (d, J = 4.8 Hz, 1 H), 7.27 (d, J = 8.0Hz, 1 H), 7.43 (s, 1 H), 7.15 min, yl}carbamate 8.47 (d, J = 5.2 Hz, 1H,). UV active  1-20 Isomer 2: ethyl [(3S)-1- 12, 17 b (400 MHz,DMSO-d₆) δ: 1.10 (t, J = 7.1 Hz, 3 H), 1.56-1.84 (m, B m/z 356(4-cyano-4- and 5 H), 1.84-2.22 (m, 7 H), 2.34 (dd, J = 9.5, 8.3 Hz, 1H), 2.64 (M + H)⁺ phenylcyclohexyl)pyrrolidin- 55 (dd, J = 9.9, 3.4, 1H), 2.74 (s, 3 H), 2.82 (td, J = 8.4 and 2.8 Hz, (ES⁺), at3-yl]methylcarbamate 1 H), 3.94 (q, J = 7.1 Hz, 2 H), 4.63 (br. s., 1H), 7.26-7.32 (m, 1 5.00 min, H), 7.34-7.45 (m, 4 H). UV active  1-21Isomer 2: ethyl [(3R)-1- 12, 18 b (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.2Hz, 3 H), 1.65-2.01 (m, B m/z 356 (4-cyano-4- and 6 H), 2.01-2.30 (m, 6H), 2.35-2.45 (m, 1 H), 2.65-2.75 (m, 1 (M + H)⁺phenylcyclohexyl)pyrrolidin- 55 H), 2.82 (s, 3 H), 2.85-2.95 (m, 1 H),4.01 (q, J = 7.2 Hz, 2 H), (ES⁺), at 3-yl]methylcarbamate 4.70 (br. s.,1 H), 7.33-7.39 (m, 1 H), 7.42-7.52 (m, 4 H). 4.94 min, B UV active 1-22 Isomer 2: ethyl {(3R)-1- 17, 28 b (500 MHz, CDCl₃) δ: 1.25 (t, J =7.0 Hz, 3 H), 1.49-1.65 (m, 2 m/z 391 [4-(5-chloropyridin-2-yl)-4- andH), 1.70-1.81 (m, 1 H), 1.82-2.02 (m, 4 H), 2.03-2.33 (m, 4 (M + H)⁺cyanocyclohexyl]pyrrolidin- 55 H), 2.34-2.55 (m, 3 H), 2.68 (dd, J =10.0, 3.0 Hz, 1 H), 2.88 (s, (ES⁺), at 3-yl}methylcarbamate 3 H), 4.11(q, J = 7.0 Hz, 2 H), 4.77-5.01 (m, 1 H), 7.50 (d, J = 4.72 min, 8.5 Hz,1 H), 7.69 (dd, J = 8.5, 2.5 Hz, 1 H), 8.54 (d, J = 2.5 Hz, UV active 1H).  2-1 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.16 (t, J= 7.0 Hz, 3 H), 1.52-1.72 (m, B m/z 358 (2′-oxo-1′,2′- and 6 H),1.93-2.43 (m, 5 H), 2.53-2.69 (m, 3 H), 2.79-2.91 (m, 1 (M + H)⁺dihydrospiro[cyclohexane- 65 H), 3.95-4.00 (m, 3 H), 6.87 (d, J = 7.5Hz, 1 H), 6.96 (td, J = (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- 7.5, 1.0Hz, 1 H), 7.20 (td, J = 7.5, 1.0 Hz, 1 H), 7.26-7.32 (m, 1 2.67 min,3-yl]carbamate H), 7.44 (d, J = 7.5 Hz, 1 H), 10.40 (s, 1 H) UV active 2-2 Isomer 1: ethyl [(3R)-1- 14 c (400 MHz, DMSO-d₆) □: 1.16 (t, J =7.0 Hz, 3 H), 1.48-1.73 (m, F m/z 358 (2′-oxo-1′,2′- and 7H), 1.95-2.11(m, 3 H), 2.27-2.31 (m, 1 H),2.61-2.81 (m,3 (M + H)⁺dihydrospiro]cyclohexane- 65 H), 2.91-2.95 (m, 1 H), 3.95-4.01 (m, 3 H),6.87 (d, J = 7.5 Hz, (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- 1 H), 6.97(t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.31- 1.62 min,3-yl[carbamate 7.33 (m, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 10.41 (s, 1 H)UV active  2-2 Isomer 2: ethyl [(3R)-1- 14 c (400 MHz, DMSO-d₆) □: 1.16(t, J = 7.0 Hz, 3 H), 1.65-1.83 (m, F m/z 358 (2′-oxo-1′,2′- and 7 H),2.02-2.13 (m, 3 H), 2.36-2.42 (m, 1 H), 2.57-2.63 (m, 2 (M + H)⁺dihydrospiro[cyclohexane- 65 H), 2.73-2.91 (m, 1 H), 3.00-3.11 (m, 1 H),3.96-4.06 (m, 3 (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- H), 6.81 (d, J =7.5 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 1.69 min,3-yl]carbamate 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.35-7.36 (m, 1H), UV active 10.27 (s, 1 H)  2-3 Isomer 1: ethyl [(3S)-1- 13 c (400MHz, DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.52-1.71 (m, F m/z 372(7′-methyl-2′-oxo-1′,2′- and 7 H), 1.96-2.09 (m, 3 H), 2.16-2.21 (m, 4H), 2.37-2.41 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 67 H), 2.66-2.56(m, 2 H), 2.82-2.86 (m, 1 H), 3.95-4.00 (m, 3 (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- H), 6.88 (t, J = 7.5 Hz, 1 H), 7.02 (d, J =7.5 Hz, 1 H), 7.24-7.29 1.63 min, 3-yl]carbamate (m, 2 H), 10.42 (s, 1H) UV active  2-4 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □:1.16 (t, J = 7.0 Hz, 3 H), 1.43-1.75 (m, F m/z 372(6′-methyl-2′-oxo-1′,2′- and 6 H), 1.92-2.10 (m, 3 H), 2.13-2.22 (m, 1H), 2.27 (s, 3 H), (M + H)⁺ dihydrospiro[cyclohexane 68 2.36-2.40 (m, 1H), 2.57-2.68 (m, 3 H), 2.82-2.86 (m, 1 H), (ES⁺) at-1,3′-indol]-4-yl)pyrrolidin- 3.95-4.00 (m, 3 H), 6.69 (s, 1 H), 6.77(d, J = 7.5 Hz, 1 H), 7.29 1.67 min, 3-yl]carbamate (m, 2 H), 10.34 (s,1 H) UV active  2-5 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □:1.16 (t, J = 7.0 Hz, 3 H), 1.51-1.71 (m, F m/z 372(5′-methyl-2′-oxo-1′,2′- and 7 H), 1.93-2.21 (m, 4 H), 2.29 (s, 3 H),2.32-2.43 (m, 1 H), (M + H)⁺ dihydrospiro[cyclohexane- 70 2.55-2.70 (m,2 H), 2.85-2.90 (m, 1 H), 3.95-4.01 (m, 3 H), (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- 6.76 (d, J = 7.5 Hz, 1 H), 7.00 (d, J = 7.5Hz, 1 H), 7.23 (s, 1 H), 1.67 min, 3-yl]carbamate 7.28 (d, J = 7.0 Hz, 1H), 10.29 (s, 1 H) UV active  2-6 Isomer 1: ethyl [(3S)-1- 13 c (400MHz, DMSO-d₆) □: 1.14-1.20(m, 4 H), 1.61-1.71 (m, 3 F m/z 372(4′-methyl-2′-oxo-1′,2′- and H), 1.95-2.44 (m, 10 H), 2.56-2.63 (m, 3H), 2.81-2.85 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 72 H), 3.95-4.01(m, 3 H), 6.60 (d, J = 7.5 Hz, 1 H), 6.70 (d, J = 7.5 (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 7.19(d, J = 6.5 Hz, 1 H), 1.73 min, 3-yl]carbamate 10.11 (s, 1 H) UV active 2-7 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.16 (t, J =7.0 Hz, 3 H), 1.52-1.70(m, F m/z 376 (6′-fluoro-2′-oxo-1′,2′- and 7 H),1.97-2.09 (m, 3 H), 2.15-2.24 (m, 1 H), 2.36-2.40 (m, 1 (M + H)⁺dihydrospiro[cyclohexane- 74 H), 2.57-2.67 (m, 2 H), 2.82-2.86 (m, 1 H),3.95-4.00 (m, 3 (ES+) at 1,3′-indol]-4-yl)pyrrolidin- H), 6.68 (dd, J =9.0, 2.5 Hz, 1 H), 6.74-6.79 (m, 1 H), 7.28 (d, J = 1.72 min,3-yl]carbamate 7.0 Hz, 1 H), 7.43 (dd, J = 8.0, 5.5 Hz, 1 H), 10.56 (bs,1 H) UV active  2-7 Isomer 2: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □:1.16 (t, J = 7.0 Hz, 3 H), 1.54-1.76 (m, F m/z 376(6′-fluoro-2′-oxo-1′,2′- and 7 H), 1.92-2.09 (m, 3 H), 2.19-2.24 (m, 1H), 2.33-2.37 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 74 H), 2.54-2.65(m, 2 H), 2.80-2.84 (m, 1 H), 3.90-4.00 (m, 3 (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- H), 6.61 (dd, J = 9.0, 2.0 Hz, 1 H),6.70-6.76 (m, 1 H), 7.27 (d, J = 1.96 min, 3-yl]carbamate 7.0 Hz, 1 H),7.33 (dd, J = 8.0, 6.0 Hz, 1 H), 10.38 (s, 1 H) UV active  2-8 Isomer 1:ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H),1.50-1.70 (m, F m/z 376 (5′-fluoro-2′-oxo-1′,2′- and 7H), 1.95-2.11 (m,3 H), 2.15-2.26 (m, 1 H), 2.39-2.43 (m, 1 (M + H)⁺dihydrospiro[cyclohexane- 76 H), 2.66-2.71 (m, 2 H), 2.79-2.83 (m, 1 H),3.95-4.00 (m, 3 (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- H), 6.86 (dd, J =8.5, 4.5 Hz, 1 H), 7.02-7.07 (m, 1 H), 7.21- 1.64 min, 3-yl]carbamate7.24 (m, 1 H), 7.30 (d, J = 7.0 Hz, 1 H), 10.42 (s, 1 H) UV active  2-8Isomer 2: ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.16 (t, J = 7.0 Hz,3 H), 1.53-1.81 (m, F m/z 376 (5′-fluoro-2′-oxo-1′,2′- and 7 H),1.89-2.09 (m, 3 H), 2.17-2.27 (m, 1 H), 2.32-2.40 (m, 1 (M + H)⁺dihydrospiro[cyclohexane- 76 H), 2.55-2.66 (m, 2 H), 2.80-2.84 (m, 1 H),3.90-4.03 (m, 3 (ES⁺) at --1,3′-indol]-4-yl)pyrrolidin- H), 6.78 (dd, J= 8.5, 4.5 Hz, 1 H), 6.95-7.00 (m, 1 H), 7.24- 1.72 min, 3-yl]carbamate7.32 (m, 2 H), 10.25 (s, 1 H) UV active  2-9 Isomer 1: ethyl [(3S)-1- 13c (400 MHz, DMSO-d₆) □: 1.14-1.20 (m, 3 H), 1.46-1.70 (m, 6 F m/z 388(6′-methoxy-2′-oxo-1′,2′- and H), 1.95-2.09 (m, 3 H), 2.13-2.23 (m, 1H), 2.36-2.40 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 78 H), 2.56-2.68(m, 2 H), 2.83-2.87 (m, 1 H), 3.19-3.25 (m, 1 (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- H), 3.73 (s, 3 H), 3.95-4.00 (m, 3 H), 6.43(d, J = 2.0 Hz, 1 H) , 1.68 min, 3-yl]carbamate 6.51 (dd, J = 8.0, 2.0Hz, 1 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.32 (d, UV active J = 8.0 Hz, 1H), 10.36 (s, 1 H)  2-10 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz,DMSO-d₆) □: 1.10-1.22 (m, 4 H), 1.53-1.70 (m, 6 F m/z 388(5′-methoxy-2′-oxo-1′,2′- and H), 1.91-2.11 (m, 2 H), 2.15-2.25 (m, 1H), 2.38-2.42 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 80 H), 2.55-2.72(m, 2 H), 2.79-2.85 (m, 1 H), 2.94-3.17 (m, 1 (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- H), 3.72 (s, 3 H), 3.95-4.00 (m, 3 H), 6.79(s, 2 H), 6.98 (s, 1 H), 1.66 min, 3-yl]carbamate 7.28 (d, J = 7.0 Hz, 1H), 10.24 (s, 1 H) UV active  2-11 Isomer 1: ethyl 65 c (400 MHz,DMSO-d₆) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.55-1.77(m,methyl[(3S)-1-(2′-oxo- and 7H), 1.99-2.10 (m, 3 H). 2.15-2.23 (m, 1 H),2.30-2.37 (m, 1 F m/z 372 1′,2′- 82 H), 2.56-2.61 (m, 1 H), 2.66-2.74(m, 2 H), 2.86-2.93 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- H), 4.03(q, J = 7.0 Hz, 2 H), 6.86 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H),7.36 (d, J = 7.5 Hz, 1 H), 1.72 min, 10.37 (s, 1 H) UV active  2-12Isomer 1: ethyl 65 c (400 MHz, MeOD-d₄) □: 1.29 (m, 3 H), 1.59-1.70 (m,2 H), 1.79- F m/z 372 methyl[(3R)-1-(2′-oxo-l′,2′- and 1.98 (m, 5 H),2.06-2.23 (m, 3 H), 2.35-2.48 (m, 1 H), 2.68- (M + H)⁺dihydrospiro[cyclohexane- 84 2.83 (m, 2 H), 2.94-3.02 (m, 5 H), 4.15 (q,J = 7.0 Hz, 2 H), 4.81- (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- 4.89 (m, 1H), 6.96 (d, J = 7.5 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 1.68 min,3-yl]carbamate H), 7.25 (t, J = 7.5 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 1 H)UV active  2-12 Isomer 2: ethyl 65 c (400 MHz, DMSO-d₆, D₂O wash) □:1.16 (t, J = 7.0 Hz, 3 H), G m/z 372 methyl[(3R)-1-(2′-oxo-l′,2′- and1.57-2.09 (m, 10 H), 2.56-2.86 (m, 7 H), 2.88-2.99 (m, 1 H), 4.00- (M +H)⁺ dihydrospiro[cyclohexane- 84 4.03 (m, 2 H), 4.57-4.75 (m, 1 H), 6.84(d, J = 7.5 Hz, 1 H), 6.96 (ES⁺) at 1,3′-indol]-4-yl)pyrrolidin- (t, J =7.5 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1.65 min,3-yl]carbamate 1 H) UV active  2-13 Isomer 1: ethyl [(3S)-1- 13 c (400MHz, DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.53-1.76 (m, F m/z 372(1′-methyl-2′-oxo-1′,2′- and 6 H), 1.95-2.12 (m, 3 H), 2.17-2.29 (m, 1H), 2.38-2.41 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 86 H), 2.56-2.70(m, 3 H), 2.83-2.87 (m, 1 H), 3.14 (s, 3 H), 3.95- (ES⁺) at1,3′-indol]-4-yl)pyrrolidin- 4.01 (m, 3 H), 7.03-7.07 (m, 2 H),7.27-7.33 (m, 2 H), 7.48 (d, 1.70 min, 3-yl]carbamate J = 7.5 Hz, 1 H)UV active  2-14 Isomer 2: ethyl 4-{(3S)-3- 13 c (400 MHz, DMSO-d₆) □:1.16 (t, J = 7.0 Hz, 3 H), 1.34 (t, J = 7.0 F m/z 430[(ethoxycarbonyl)amino and Hz, 3 H), 1.59-1.83 (m, 4 H), 1.95-2.11 (m, 2H), 2.21-2.43 (M + H)⁺ [pyrrolidin-1-yl}-2′- 87 (m, 6 H), 2.60-2.73 (m,2 H), 2.79-2.84 (m, 1 H), 3.96-4.00 (ES⁺) at oxospiro]cyclohexane- (m, 3H), 4.37 (q, J = 7.0 Hz, 2 H), 7.21-7.38 (m, 3 H), 7.52 1.82 min,1,3′-indole]-1′(2′ H)- (d, J = 7.5 Hz, 1 H), 7.85 (d, J = 7.5 Hz, 1 H)UV active carboxylate  2-15 Isomer 1: ethyl {(3S)-1- 13 c (400 MHz,DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.61-1.70 (m, G m/z 415[1′-(2-amino-2-oxoethyl)- and 7 H), 1.95-2.13 (m, 3 H), 2.21-2.31 (m, 1H), 2.37-2.44 (m, 1 (M + H)⁺ 2′-oxo-1′,2′- 88 H), 2.58-2.66 (m, 2 H),2.84-2.88 (m, 1 H), 3.96-4.01 (m, 3 (ES⁺) at dihydrospiro[cyclohexane-H), 4.26 (s, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 14.40 min, 1,3′-indol]-4-yl]pyrrolidin- H), 7.23-7.32 (m, 3 H), 7.48 (d,J = 7.5 Hz, 1 H), 7.62 (s, 1 H) UV active 3-yl}carbarrate  2-15 Isomer2: ethyl {(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H),1.54-1.84 (m, G m/z 415 [1′-(2-amino-2-oxoethyl)- and 7 H), 1.91-2.12(m, 3 H), 2.19-2.28 (m, 1 H), 2.35-2.43 (m, 1 (M + H)⁺ 2′-oxo-1′,2′- 88H), 2.56-2.66 (m, 2 H), 2.77-2.90 (m, 1 H), 3.95-4.00 (m, 3 (ES⁺) atdihydrospiro[cyclohexane- H), 4.23 (s, 2 H), 6.83 (d, J = 7.5 Hz, 1 H),7.01 (t, J = 7.5 Hz, 1 4.88 min, 1,3′-indol]-4-yl]pyrrolidin- H),7.19-7.35 (m, 4 H), 7.61 (s, 1 H) UV active 3-yl}carbarrate  2-16 Isomer1: ethyl [(3S)-1- 13 c (400 MHz, (MSO-d₆, D₂O wash) □: 1.15(t, J = 7.0Hz, 3 H), 1.53- F m/z 360 (2′-oxo-1′,2′- and 1.79 (m, 7 H), 2.21-2.36(m, H), 2.59-2.73 (m, 5 H), 2.89- (M + H)⁺ dihydrospiro[cyclohexane-2.97 (m, 1 H), 3.92-4.03 (m, 3 H), 6.97 (dd, J = 7.5, 5.5 Hz, 1 (ES⁺) at1,3′-pyrrolo]2,3- 90 H), 7.24-7.29 (m, 1 H), 7.82 (d, J = 7.5 Hz, 1 H),8.08 (d, J = 5.5 1.48 min, b]pyridin]-4-yl)pyrrolidin- Hz, 1 H). UVactive 3-yl]carbamate  2-17 Isomer 1: ethyl [(3S)-1- 13 c (400 MHz,DMSO-d₆) □: 1.16 (t, J = 7.0 Hz, 3 H), 1.47-1.77 (m, F m/z 393(5′-chloro-2′-oxo-1′,2′- and 6 H), 1.94-2.12 (m, 3 H), 2.14-2.26 (m, 1H), 2.36-2.45 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane- 93 H), 2.55-2.63(m, 2 H), 2.64-2.73 (m, 1 H), 2.78-2.90 (m, 1 (ES⁺) at 1,3′-pyrrolo[2,3-H), 3.91-4.09 (m, 3 H), 2.28 (d, J = 6.5 Hz, 1 H), 7.77 (s, 1 H), 1.61min, b]pyridin]-4-yl)pyrrolidin- 8.16 (d, J = 2.0 Hz, 1 H), 11.24 (s, 1H) UV active 3-yl]carbamate  2-18 Isomer 1: ethyl 84 c (400 MHz,DMSO-d₆) □: 1.19 (t, J = 7.0 Hz, 3 H), 1.55-1.77 (m, G m/z 373methyl[(3R)-1-(2′-oxo- and 7 H), 1.98-2.09 (m, 3 H), 2.34-2.38 (m, 1 H),2.44-2.48 (m, 1 (M + H)⁺ 1′,2′- 90 H), 2.56-2.63 (m, 2 H), 2.68-2.72 (m,1 H), 2.84-2.92 (m, 4 (ES⁺) at dihydrospiro[cyclohexane- H), 4.03 (q, J= 7.0 Hz, 2 H), 6.98 (dd, J = 7.5, 5.5 Hz, 1 H), 7.71- 4.68 min,1,3′-pyrrolo[2,3- 7.73 (m, 1 H), 8.08 (dd, J = 5.5, 1.5 Hz, 1 H), 11.01(s, 1 H) UV active b]pyridin]-4-yl)pyrrolidin- 3-yl]carbamate  2-18Isomer 2: ethyl 84 c (400 MHz, DMSO-d₆, D₂O wash) □:1.17 (t, J = 7.0 Hz,3 H), G m/z 373 methyl[(3R)-1-(2′-oxo- and 1.43-1.59 (m, 2 H), 1.64-2.09(m, 7 H), 2.18-2.36 (m, 2 H), 2.40- (M + H)⁺ 1′,2′- 90 2.47 (m, 1 H),2.54-2.61 (m, 2 H), 2.64-2.71 (m, 1 H), 2.78- (ES⁺) atdihydrospiro[cyclohexane- 2.92 (m, 4 H), 4.01 (q, J = 7.0 Hz, 2 H), 6.95(dd, J = 7.0, 5.5 Hz, 5.11 min, 1,3′-pyrrolo[2,3- 1 H), 7.74-7.76 (m, 1H), 8.03-8.04 (m, 1 H) UV active b]pyridin]-4-yl)pyrrolidin-3-yl]carbamate  2-19 Isomer 1: ethyl [(3S)-1- 13 g (400 MHz, CDCl₃) □ □:1.27-1.31 (m, 4 H), 1.67-1.85 (m, 5 H), L m/z 389(5′-methoxy-2′-oxo-1′,2′- and 1.96-2.20 (m, 6 H), 2.77-2.87 (m, 1 H),3.32-3.77 (m, 4 H), (M + H)⁺ dihydrospiro[cyclohexane 95 3.93 (s, 3 H),4.16 (q, J = 7.0 Hz, 2 H), 7.03 (s, 1 H), 7.35 (s, 1 (ES⁺) at-1,3′-pyrrolo[2,3- H), 7.77 (s, 1 H) 4.00 min,c]pyridin]-4-yl)pyrrolidin- UV active 3-yl]carbamate  2-20 Isomer 1:ethyl [(3S)-1- 13 c (400 MHz, DMSO-d₆) □: 1.15 (t, J = 7.0 Hz, 3 H),1.55-1.82(m, F m/z 389 (5′-methoxy-2′-oxo-1′,2′- and 7 H), 1.98-2.16 (m,3 H), 2.26-2.31 (m, 1 H), 2.35-2.39 (m, 1 (M + H)⁺dihydrospiro[cyclohexane- 97 H), 2.62-2.65 (m, 2 H), 2.92 (t, J = 8.0Hz, 1 H), 3.82 (s, 3 H), (ES⁺) at 1,3′-pyrrolo[3,2- 3.88-4.05 (m, 3 H),6.65 (d, J = 8.5 Hz, 1 H), 7.21-7.24 (m, 2 1.64 min,b]pyridin]-4-yl)pyrrolidin- H), 10.30 (s, 1 H) UV active 3-yl]carbamate 2-21 Isomer 2: ethyl 84 c (400 MHz, DMSO-d₆) □: 1.19 (t, J = 7.0 Hz, 3H), 1.60-1.79 (m, F m/z 373 methyl[(3R)-1-(2′-oxo- and 5 H), 1.85-2.22(m, 6 H), 2.30-2.41 (m, 1 H), 2.56-2.70 (m, 3 (M + H)⁺ 1′,2′- 99 H),2.82-2.91 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.19 (m, 2 H), (ES⁺) atdihydrospiro[cyclohexane- 8.10-8.12 (m, 1 H), 10.57 (s, 1 H) 1.64 min,1,3′-pyrrolo[3,2- UV active b]pyridin]-4-yl)pyrrolidin- 3-yl]carbamate 3-1 Mixture of isomers: ethyl 12 a (400 MHz, CDCl₃) δ: 1.27 (t, J = 7.0Hz, 3 H), 1.75-1.98 (m, 8 B m/z 356 4-(4-cyano-4- and H), 2.22-2.24 (m,2 H), 2.58-2.64 (m, 1 H), 2.70-2.82 (m, 4 (M + H)⁺phenylcyclohexyl)-1,4- 32 H), 3.46-3.56 (m, 4 H), 4.15 (q, J = 7.0,2 H),7.28-7.33 (m, 1 (ES⁺), at diazepane-1-carboxylate H), 7.35-7.42 (m, 2H), 7.47-7.51 (m, 2 H). 4.25 and 4.50 min, UV active  3-2 Mixture ofisomers: ethyl 20 a (400 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.0,3 H),1.61-1.72 (m, 4 B m/z 374 4-[4-cyano-4-(3- and H), 1.86-1.96 (m, 4 H),2.04-2.09 (m, 2 H), 2.61-2.72 (m, 5 (M + H)⁺ fluorophenyl)cyclohexyl]-32 H), 3.38-3.42 (m, 4 H), 4.04 (q, J = 7.02, 2 H), 7.19-7.24 (m, 1(ES⁺), at 1,4-diazepane-1- H), 7.36-7.40 (m, 2 H), 7.46-7.54 (m, 1 H).2.54 and carboxylate 2.68 min, UV active  3-3 Mixture of isomers: ethyl21 a (400 MHz, CDCl₃) δ: 1.26 (t, J = 7.0, 3 H), 1.76-1.98 (m, 8 H), Bm/z 374 4-[4-cyano-4-(4- and 2.20-2.23 (m, 2 H), 2.55-2.65 (m, 1 H),2.68-2.81 (m, 4 H), (M + H)⁺ fluorophenyl)cyclohexyl]- 32 3.46-3.53 (m,4 H), 4.14 (q, J = 7.0, 2 H), 7.05-7.11 (m, 2 H), (ES⁺), at1,4-diazepane-1- 7.43-7.47 (m, 2 H). 2.49 and carboxylate 2.67 min, UVactive  3-4 Mixture of isomers: ethyl 32 a (400 MHz, CDCl₃) δ: 1.27 (t,J = 7.0 Hz, 3 H), 1.75-1.98 (m, 8 A m/z 390 4-[4-cyano-4-(2- and H),2.57-2.61 (m, 3 H), 2.72-2.83 (m, 4 H), 3.47-3.55 (m, 4 (M + H)⁺chlorophenyl)cyclohexyl]- 35 H), 4.15 (q, J = 7.0, 2 H), 7.29-7.33 (m, 2H), 7.43-7.46 (m, 2 H). (ES⁺), at 1,4-diazepane-1- 1.79 and carboxylate1.89 min, UV active  3-5 Mixture of isomers: ethyl 24 a (400 MHz,DMSO-d₆) δ: 1.18 (t, J = 7.0,3 H), 1.60-1.70 (m, 4 B m/z 3904-[4-cyano-4-(3- and H), 1.86-1.97 (m, 4 H), 2.03-2.05 (m, 2 H),2.62-2.73 (m, 5 (M + H)⁺ chlorophenyl)cyclohexyl]- 32 H), 3.38-3.43 (m,4 H), 4.04 (q, J = 7.0, 2 H), 7.43-7.49 (m, 4H). (ES⁺), at1,4-diazepane-1- 2.48 and carboxylate 2.72 min, UV active  3-6 Mixtureof isomers: ethyl 32 a (400 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.0,3 H),1.60-1.70 (m, 4 B m/z 390 4-[4-cyano-4-(4- and H), 1.87-1.94 (m, 4 H),2.09-2.10 (m, 2 H), 2.62-2.73 (m, 5 (M + H)⁺ chlorophenyl)cyclohexyl]-36 H), 3.38-3.41 (m, 4 H), 4.03 (q, J = 7.02, 2 H), 7.46-7.56 (m, 4H).(ES⁺), at 1,4-diazepane-1- 2.68 and carboxylate 2.86 min, UV active  3-7Mixture of isomers: ethyl 22 a (400 MHz, CDCl₃) δ: 1.27 (t, J = 7.0 Hz,3 H), 1.77-1.97 (m, 8 B m/z 370 4-[4-cyano-4-(2- and H), 2.43-2.46 (m, 2H), 2.57-2.63 (m, 1 H), 2.64 (s, 3 H), 2.67- (M + H)⁺methylphenyl)cyclohexyl- 32 2.84 (m, 4 H), 3.47-3.55 (m, 4 H), 4.15 (q,J = 7.0 Hz, 2 H), 7.20- (ES⁺), at 1,4-diazepane-1- 7.29 (m, 4 H). 2.57min, carboxylate UV active  3-8 Mixture of isomers: ethyl 23 a (400 MHz,CDCl₃) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.77-1.97 (m, 8 B m/z 3704-[4-cyano-4-(3- and H), 2.20-2.23 (m, 2 H), 2.37 (s, 3 H), 2.58-2.62(m, 1 H), 2.72- (M + H)⁺ methylphenyl)cyclohexyl- 32 2.82 (m, 4 H),3.47-3.54 (m, 4 H), 4.14 (q, J = 7.0 Hz, 2 H), 7.12- (ES⁺), at1,4-diazepane-1- 7.17 (m, 1 H), 7.25-7.29 (m, 3 H). 2.35 and carboxylate2.48 min, UV active  3-9 Mixture of isomers: ethyl 32 a (400 MHz,DMSO-d₆) δ: 1.18 (t, J = 7.0 Hz, 3 H), 1.60-1.72 (m, B m/z 3864-[4-cyano-4-(4- and 4 H), 1.83-1.91 (m, 4 H), 2.09-2.12 (m, 3 H),2.62-2.71 (m, 5 (M + H)⁺ methoxyphenyl)cyclohexyl]- 37 H), 3.38-3.41 (m,4 H), 3.76 (s, 3 H), 4.04 (q, J = 7.02, 2 H), (ES⁺), at 1,4-diazepane-1-6.96-7.02 (m, 2 H), 7.42-7.44 (m, 2 H). 2.47 and carboxylate 2.60 min,UV active  3-10 Mixture of isomers: ethyl 32 a (400 MHz, CDCl₃) δ: 1.27(t, J = 6.8 Hz, 3 H), 1.78-1.97 (m, 8 E m/z 424 4-[4-cyano-4-[2- and H),2.42-2.78 (m, 7 H), 3.46-3.64 (m, 4 H), 4.14-4.16 (m, 2 (M + H)⁺(trifluoromethyl)phenyl] 38 H), 7.49-7.52 (m, 1 H), 7.57-7.59 (m, 1 H),7.66-7.69 (m, 1 (ES⁺), at cyclohexyl}-1,4-diazepane- H), 7.80-7.82 (m, 1H). 5.11 min, 1-carboxylate UV active  3-11 Mixture of isomers: ethyl 26a (400 MHz, CDCl₃) δ: 1.21-1.28 (m, 3 H), 1.75-1.88 (m, 4 H), B m/z 3574-[4-cyano-4-(pyridin-2-yl) and 1.95-1.99 (m, 2 H), 2.07-2.21 (m, 3 H),2.53-2.68 (m, 2 H), (M + H)⁺ cyclohexyl]-1,4- 32 2.69-2.82 (m, 4 H),3.46-3.55 (m, 4 H), 4.14 (m, 2 H), 7.23-7.26 (ES⁺), atdiazepane-1-carboxylate (m, 1 H), 7.53-7.62 (m, 1 H), 7.71-7.74 (m, 1H), 8.58-8.64 3.33 and (m, 1 H). 3.49 min, UV active  3-12 Mixture ofisomers: ethyl 32 a (400 MHz, CDCl₃) δ: 1.27 (t, J = 6.8 Hz, 3 H),1.647-1.99 (m, 8 E m/z 357 4-[4-cyano-4-(pyridin-4- and H), 2.19-2.26(m, 2 H), 2.65-2.93 (m, 5 H), 3.49-3.56 (m, 4 (M + H)⁺yl)cyclohexyl]-1,4- 40 H), 4.13-4.16 (m, 2 H), 7.37-7.39 (m, 2 H),8.64-8.66 (m, 2 H). (ES⁺), at diazepane-1-carboxylate 4.10 min, UVactive  3-13 Isomer 1: ethyl 4-[4-(3- 32 a (400 MHz, CDCl₃) δ: 1.25-1.27(m, 3 H), 1.78-2.16 (m, 10 H), B m/z 391 chloropyridin-2-yl)-4- and2.55-2.79 (m, 5 H), 3.48-3.61 (m, 4 H), 4.13-4.17 (m, 2 H), (M + H)⁺cyanocyclohexyl]-1,4- 41 7.26-7.27 (m, 1 H), 7.74-7.76 (m, 1 H),8.46-8.49 (m, 1 H). (ES⁺), at diazepane-1-carboxylate 3.88 min, UVactive  3-14 Mixture of isomers: ethyl 29 a (400 MHz, DMSO-d₆) δ:1.16-1.24 (m, 3 H), 1.61-1.68 (m, 5 H), C m/z 3714-[4-(4-methylpyridin-2- and 1.85-2.01 (m, 3 H), 2.13-2.18 (m, 1 H),2.36 (s, 1.5 H), 2.38 (s, (M + H)⁺ yl)-4-cyanocyclohexyl]- 32 1.5 H),2.58-2.77 (m, 6 H), 3.38-3.44 (m, 4 H), 3.95-4.03 (m, (ES⁺), at1,4-diazepane-1- 2 H), 7.20-7.23 (m, 1 H), 7.41-7.46 (m, 1 H), 8.43-8.48(m, 1 H). 1.81 min, carboxylate UV active  3-15 Mixture of isomers:ethyl 27 e (400 MHz, DMSO-d₆) δ: 1.27 (t, J = 7.0 Hz, 3 H), 1.57-1.77(m, B m/z 375 4-[4-(5-fluoropyridin-2-yl)- and 4 H), 1.85-2.03 (m, 4 H),2.12-2.21 (m, 2 H), 2.59-2.74 (m, 5 (M + H)⁺ 4-cyanocyclohexyl]-1,4- 31H), 3.38-3.42 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.66-7.70 (m, (ES⁺),at diazepane-1-carboxylate 1 H), 7.80-7.86 (m, 1 H), 8.61-8.63 (m, 1 H).3.64 min, UV active  3-16 Mixture of isomers: ethyl 28 a (400 MHz,DMSO-d₆) δ: 1.15-1.23 (m, 3 H), 1.58-1.69 (m, 4 H), B m/z 3914-[4-(5-chloropyridin-2- and 1.85-1.99 (m, 4 H), 2.14-2.19 (m, 2 H),2.59-2.73 (m, 5 H), (M + H)⁺ yl)-4-cyanocyclohexyl]- 32 3.38-3.45 (m, 4H), 4.00-4.05 (m, 2 H), 7.63-7.65 (m, 1 H), (ES⁺), at 1,4-diazepane-1-8.01-8.04 (m, 1 H), 8.65-8.67 (m, 1 H). 4.06 min, carboxylate UV active 3-17 Isomer 1: ethyl 4-[4-(5- 32 a (400 MHz, DMSO-d₆) δ: 1.18 (t, J =7.0 Hz, 3 H), 1.55-1.75 (m, B m/z 435 bromopyridin-2-yl)-4- and 4 H),1.83-2.02 (m, 4 H), 2.09-2.24 (m, 2 H), 2.57-2.66 (m, 2 and 437cyanocyclohexyl]-1,4- 42 H), 2.67-2.80 (m, 2 H), 3.35-3.44 (m, 5 H),4.03 (q, J = 7.0 Hz, (M + H)⁺ diazepane-1-carboxylate 2 H), 7.59 (dd, J= 8.5, 0.8 Hz, 1 H), 8.15 (dd, J = 8.5, 2.5 Hz, 1 (ES⁺), at H), 8.75(dd, J = 2.5, 0.8 Hz, 1 H). 4.15, UV active  3-18 Mixture of isomers:ethyl 32 a (400 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.2 Hz, 3 H), 1.56-1.68(m, B m/z 371 4-[4-(5-methylpyridin-2- and 4 H), 1.85-2.01 (m, 4 H),2.11-2.16 (m, 2 H), 2.29 (s, 3 H), (M + H)⁺ yl)-4-cyanocyclohexyl]- 432.57-2.75 (m, 5 H), 3.38-3.44 (m, 4 H), 4.02 (q, J = 7.2 Hz, 2 (ES⁺), at1,4-diazepane-1- H), 7.44-7.48 (m, 1 H), 7.67-7.69 (m, 1 H), 8.40-8.43(m, 1 H). 4.31 and carboxylate 4.50 min, UV active  3-19 Isomer 2: ethyl4-[4-(5- 32 a (400 MHz, DMSO-d₆) δ: 1.12-1.16 (m, 3 H), 1.56-1.68 (m, 6H), B m/z 387 methoxypyridin-2-yl)-4- and 1.88-1.95 (m, 2 H), 2.12-2.18(m, 2 H), 2.56-2.70 (m, 5 H), (M + H)⁺ cyanocyclohexyl]-1,4- 443.38-3.42 (m, 4 H), 3.86 (s, 3 H), 3.96-4.02 (m, 2 H), 7.45- (ES⁺), atdiazepane-1-carboxylate 7.49 (m, 1 H), 7.55-7.59 (m, 1 H), 8.34-8.35 (m,1 H). 3.66 min, UV active  3-20 Isomer 2: ethyl 4-[4- 32 a (400 MHz,DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), 1.34 (t, J = 7.0 B m/z 401cyano-4-(5-ethoxypyridin- and Hz, 3 H), 1.58-1.67 (m, 4 H), 1.85-1.94(m, 4 H), 2.14-2.18 (M + H)⁺ 2-yl)cyclohexyl]-1,4- 45 (m, 2 H),2.62-2.73 (m, 5 H), 3.30-3.41 (m, 4 H), 4.03 (q, J = (ES⁺), atdiazepane-1-carboxylate 7.0 Hz, 2 H), 4.11 (q, J = 7.0 Hz, 2 H),7.42-7.45 (m, 1 H), 7.48- 4.07 min, 7.51 (m, 1 H), 8.28-8.29 (m, 1 H).UV active  3-21 Mixture of isomers: ethyl 32 a (400 MHz, DMSO-d₆) δ:1.16 (t, J = 7.2 Hz, 3 H), 1.32-1.34 (m, B m/z 425 4-{4-cyano-4[5- and 2H), 1.58-1.80 (m, 6 H), 1.98-2.03 (m, 2 H), 2.62-2.73 (m, 5 (M + H)⁺(trifluoromethyl)pyridin-2- 46 H), 3.30-3.41 (m, 4 H), 4.03 (q, J = 7.2Hz, 2 H), 7.88-7.90 (m, (ES⁺), at yl]cyclohexyl}-1,4- 1 H), 8.32-8.35(m, 1 H), 9.07 (s, 1 H). 4.31 and diazepane-1-carboxylate 4.50 min, UVactive  3-22 Mixture of isomers: ethyl 30 a (400 MHz, CDCl₃) δ:1.22-1.27 (m, 3 H), 1.62-2.04 (m, 6 H), E m/z 3714-[4-(6-methylpyridin-2- and 2.10-2.49 (m, 4 H), 2.53 (s, 2.4 H), 2.55(s, 0.6 H), 2.62-2.85 (M + H)⁺ yl)-4-cyanocyclohexyl]- 32 (m, 5 H),3.42-3.56 (m, 4 H), 4.13-4.17 (m, 2 H), 7.05-7.09 (ES⁺), at1,4-diazepane-1- (m, 1 H), 7.35-7.40 (m, 1 H), 7.56-7.60 (m, 1 H). 4.55and carboxylate 4.63 min, UV active  3-23 Mixture of isomers: ethyl 32 a(400 MHz, CDCl₃) δ: 1.24-1.28 (m, 3 H), 1.68-2.40 (m, 10 H), D m/z 4254-{4-cyano-4-[6- and 2.56-3.01 (m, 5 H), 3.38-3.54 (m, 4 H), 4.12-4.21(m, 2 H), (M + H)⁺ (trifluoromethyl)pyridin-2- 47 7.65-7.69 (m, 1 H),7.83-7.87 (m, 1 H), 7.95-7.99 (m, 1 H). (ES⁺), at yl]cyclohexyl}-1,4-6.11 and diazepane-1-carboxylate 6.22 min, UV active  3-24 Isomer 1:ethyl 4-[4- 32 a (400 MHz, CDCl₃) δ: 1.27 ((t, J = 7.2 Hz, 3 H),1.70-2.01 (m, 8 B m/z 362 cyano-4-(thiophen-2- and H), 2.38-2.48 (m, 2H), 2.53-2.85 (m, 5 H), 3.44 (m, 4 H), 4.15 (M + H)⁺ yl)cyclohexyl]-1,4-48 (q, J = 7.2 Hz, 2 H), 6.97-6.99 (m, 1 H), 7.11-7.14 (m, 1 H), (ES⁺),at diazepane-1-carboxylate 7.27-7.28 (m, 1 H). 4.03 min, UV active  3-25Mixture of isomers: ethyl 12 a (400 MHz, CDCl₃) δ: 1.09-1.26 (m, 3 H),1.47-1.70 (m, 2 H), B m/z 374 4-(4-cyano-4- and 1.73-1.99 (4 H, m), 2.08(d, J = 11.9, 2 H), 2.58-2.72 (m, 2 H), (M + H)⁺ phenylcyclohexyl)-6- 342.72-3.02 (m, 3 H), 3.24-3.36 (m, 1 H), 3.36-3.60 (m, 2 H), (ES⁺), atfluoro-1,4-diazepane-1- 3.71 (qd, J = 14.8, 5.0, 1 H), 4.01 (d, J =11.9, 2 H), 4.56-4.86 4.56 min, carboxylate (m, 1 H), 7.21-7.35 (m, 1H), 7.35-7.44 (m, 2 H), 7.44-7.56 UV active (m, 2 H).  3-26 Mixture ofisomers: ethyl 12 a (400 MHz, CDCl₃) δ: 1.21-1.33 (m, 5 H), 1.81-2.08(m, 6 H), B m/z 372 4-(4-cyano-4- and 2.19-2.31 (m, 2 H), 2.60-2.89 (m,4 H), 2.91-3.02 (m,1 H), (M + H)⁺ phenylcyclohexyl)-6- 33 3.42-3.72 (m,3 H), 3.89-4.00 (m, 1 H), 4.15 (qd, J = 6.9, 2.8 (ES⁺), athydroxy-1,4-diazepane- Hz, 2 H), 7.30-7.36 (m, 1 H), 7.39 ( t, J = 7.5Hz, 2 H) 7.46- 3.66 min, 1-carboxylate 7.51 (m, 2 H) UV active  3-27Mixture of isomers: ethyl 28 a (400 MHz, DMSO-d₆) δ: 1.04-1.28 (m, 3 H),1.46-1.76 (m, 3 H), B m/z 409 4-[4-(5-chloropyridin-2- and 1.83-2.07 (m,3 H), 2.18-2.20 (m, 1 H), 2.51-2.87 (m, 7 H), (M + H)⁺yl)-4-cyanocyclohexyl]-6- 34 3.36-3.63 (m, 2 H), 3.65-3.78 (m, 1 H),3.90-4.13 (m, 2 H), (ES⁺), at fluoro-1,4-diazepane-1- 4.52-4.83 (m, 1H), 7.56-7.76 (m, 1 H), 8.05 (ddd, J = 8.6, 6.2, 4.36 min, carboxylate2.8 Hz, 1 H), 8.69 (dd, J = 17.3, 2.3 Hz, 1 H). UV active  3-28 Mixtureof isomers: 12, 31 d (400 MHz, CDCl₃) δ: 1.61-2.01 (m, 7 H), 2.10-2.50(m, 3 H), B m/z 342 methyl 4-(4-cyano-4- and 2.62-3.02 (m, 4 H),3.24-3.61 (m, 4 H), 3.71 (s, 3 H), 7.32- (M + H)⁺ phenylcyclohexyl)-1,4-56 7.53 (m, 5 H). (ES⁺), at diazepane-1-carboxylate 3.78 min, UV active 3-29 Mixture of isomers: 2- 12, 31 d (400 MHz, CDCl₃) δ: 1.53-2.41 (m,11 H), 2.60-3.11 (m, 4 H), B m/z 374 fluoroethyl 4-(4-cyano-4- and3.47-3.73 (m, 4 H), 4.40 (d, J = 29.2, 2 H), 4.64 (d, J = 47.6, 2 (M +H)⁺ phenylcyclohexyl)-1,4- 64 H), 7.32-7.53 (m, 5 H). (ES⁺), atdiazepane-1-carboxylate 3.98 min, UV active  3-30 Isomer 1:but-2-yn-1-yl 4- 31, 40 e (400 MHz, DMSO-d₆) δ: 1.50-1.71 (m, 4 H), 1.80(s, 3 H), 1.85- B m/z 381 [4-cyano-4-(pyridin-4- and 1.95 (m, 4 H),2.11-2.16 (m, 2 H), 2.62-2.74 (m, 5 H), 3.39- (M + H)⁺yl)cyclohexyl]-1,4- 58 3.43 (m, 4 H), 4.63-4.65 (m, 2 H), 7.54-7.56 (m,2 H), 8.62- (ES⁺), at diazepane-1-carboxylate 8.64 (m, 2 H). 3.28 min,UV active  3-31 Isomer 1: prop-2-yn-1-yl 31, 44 e (400 MHz, DMSO-d₆) δ:1.55-1.71 (m, 4 H), 1.84-1.95 (m, 4 H), C m/z 397 4-[4-cyano-4-(5- and2.14-2.19 (m, 2 H), 2.58-2.76 (m, 5 H), 3.39-3.52 (m, 4 H), (M + H)⁺methoxypyridin-2- 57 3.84 (s, 3 H), 4.58-4.61 (m, 1 H), 4.67-4.68 (m, 2H), 7.43-7.47 (ES⁺), at yl)cyclohexyl]-1,4- (m, 1 H), 7.50-7.53 (m, 1H), 8.30-8.31 (m, 1 H). 5.82 min, diazepane-1-carboxylate UV active 3-32 Isomer 1: but-2-yn-1-yl 4- 31, 49 e (400 MHz, DMSO-d₆) δ:1.59-1.70 (m, 4 H), 1.82-1.83 (m, 3 H), B m/z 411 [4-cyano-4-(5- and1.83-1.95 (m, 4 H), 2.14-2.19 (m, 2 H), 2.58-2.74 (m, 5 H), (M + H)⁺methoxypyridin-2- 58 3.39-3.44 (m, 4 H), 3.84 (s, 3 H), 4.62-4.64 (m, 2H), 7.43-7.47 (ES⁺), at yl)cyclohexyl]-1,4- (m, 1 H), 7.50-7.53 (m, 1H), 8.30-8.31 (m, 1 H). 3.80 min, diazepane-1-carboxylate UV active 3-33 Isomer 2: ethyl 4-[4- 32 a (400 MHz, CDCl₃) δ: 1.26 (t, J = 7.2Hz, 3 H), 1.60-2.00 (m, 10 B m/z 389 (methoxycarbonyl)-4- and H),2.50-2.85 (m, 5 H), 3.42-3.58 (m, 4 H), 3.66 (s, 3 H), 4.14 (M + H)⁺phenylcyclohexyl]-1,4- 49 (q, J = 7.0 Hz, 2 H), 7.22-7.24 (m, 1 H),7.28-7.36 (m, 4 H). (ES⁺), at diazepane-1-carboxylate 4.36 min, UVactive  3-34 Mixture of isomers: ethyl 32 a (400 MHz, CDCl₃) δ:1.23-1.28 (m, 3 H), 1.62-2.08 (m, 10 H), D m/z 4244-[4-(3-chloropyridin-2- and 2.48-2.79 (m, 5 H), 3.42-3.56 (m, 4 H),3.64 (s, 1.4 H), 3.68 (s, (M + H)⁺ yl)-4-(methoxycarbonyl) 50 1.6 H),4.12-4.16 (m, 2 H), 7.15-7.19 (m, 1 H), 7.61-7.64 (m, (ES⁺), atcyclohexyl]-1,4-diazepane- 1 H), 8.44-8.51 (m, 1 H). 5.49 and1-carboxylate 5.54 min, UV active  4-1 Isomer 2: methyl 4-(2′- 65 c (400MHz, DMSO-d₆) □: 1.51-1.82 (m, 8 H), 2.06-2.19 (m, 2 P m/z 358oxo-1′,2′- and H), 2.61-2.78 (m, 5 H), 3.39-3.43 (m, 4 H), 3.59 (s, 3H), 6.78 (M + H)⁺ dihydrospiro[cyclohexane- 104 (d, J = 7.5 Hz, 1 H),6.94 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.5 Hz, (ES⁺) at1,3′-indol]-4-yl)-1,4- 1 H), 7.21 (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H)1.86 min, diazepane-1-carboxylate UV active  4-2 Isomer 1: ethyl4-(2′-oxo- 32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.42-1.53 (m, P m/z 372 1′,2′- and 2 H), 1.67-1.82 (m, 8 H), 2.62-2.86(m, 5 H), 3.39-3.48 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 65 H), 4.04(q, J = 7.0 Hz, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.98 (t, J = (ES⁺) at1,3′-indol]-4-yl)-1,4- 7.5 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.50 (d,J = 7.5 Hz, 1 H), 1.90 min, diazepane-1-carboxylate 10.42 (s, 1 H) UVactive  4-2 Isomer 2: ethyl 4-(2′-oxo- 32 c (400 MHz, DMSO-d₆) □: 1.18(t, J = 7.0 Hz, 3 H), 1.51-1.60 (m, P m/z 372 1′,2′- and 2 H), 1.62-1.83(m, 6 H), 2.06-2.19 (m, 2 H), 2.61-2.78 (m, 5 (M + H)⁺dihydrospiro[cyclohexane- 65 H), 3.38-3.42 (m, 4 H), 4.04 (q, J = 7.0Hz, 2 H), 6.79 (d, J = 7.5 (ES⁺) at 1,3′-indol]-4-yl)-1,4- Hz, 1 H),6.94 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.20 1.94 min,diazepane-1-carboxylate (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H) UV active 4-3 Isomer 2: 4-(4-butanoyl- 65 (400 MHz, DMSO-d₆) □: 0.89 (t, J = 7.5Hz, 3 H), 1.37-1.80 (m, P m/z 370 1,4-diazepan-1- and c 11 H), 2.05-2.34(m, 4 H), 2.59-2.84 (m, 4 H), 3.42-3.55 (m, (M + H)⁺yl)spiro[cyclohexane-1,3′- 105 4 H), 6.79 (d, J = 7.5 Hz, 1 H), 6.94 (t,J = 7.5 Hz, 1 H), 7.14 (t, J = (ES⁺) at indol]-2′(1′ H)-one 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1 H), 10.26 (s, 1 H) 1.92 min, UV active  4-4Isomer 2: 4-{4-[(2E)-but- 65 (400 MHz, MeOD-d₄) □: 1.72-1.96 (m, 11 H),2.24-2.34 (m, 2 F m/z 368 2-enoyl]-1,4-diazepan-1-, and c H), 2.76-2.83(m, 3 H), 2.92-2.96 (m, 2 H), 3.60-3.71 (m, 4 (M + H)⁺yl}spiro[cyclohexane-1 ,3- H), 6.44-6.49 (m, 1 H), 6.81-6.91 (m, 2 H),7.01 (t, J = 7.5 Hz, (ES⁺) at indol]-2′(1′ H)-one 107 1 H), 7.18 (t, J =8.0 Hz, 2 H) 1.62 min, UV active  4-5 Isomer 2: ethyl 4-(7′- 32 (400MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.54-1.78 (m, F m/z 387methyl-2′-oxo-1′,2′- and c 8 H), 2.08-2.21 (m, 5 H), 2.74-2.66 (m, 5 H),3.37-3.42 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 67 H), 4.03 (q, J =7.0 Hz, 2 H), 6.85 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = (ES⁺) at1,3′-indol]-4-yl)-1,4- 7.5 Hz, 1 H), 7.01 (d, J = 7.5 Hz, 1 H). NH notobserved. 1.72 min, diazepane-1-carboxylate UV active  4-6 Isomer 1:ethyl 4-(6′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.43-1.47 (m, F m/z 386 methyl-2′-oxo-1′,2′- and c 2 H), 1.71-1.76 (m, 8H), 2.28 (s, 3 H), 2.59-2.79 (m, 5 H), (M + H)⁺dihydrospiro[cyclohexane- 68 3.40-3.43 (m, 4 H), 4.04 (q, J = 7.0 Hz, 2H), 6.70 (s, 1 H), 6.78 (ES⁺) at 1,3′-indol]-4-yl)-1,4- (d, J = 7.5 Hz,1 H), 7.37 (d, J = 7.5 Hz, 1 H), 10.36 (s, 1 H) 1.72 min,diazepane-1-carboxylate UV active  4-6 Isomer 2: ethyl 4-(6′- 32 (400MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.77 (m, F m/z 386methyl-2′-oxo-1′,2′- and c 8 H), 2.05-2.16 (m, 2 H), 2.25 (s, 3 H),2.65-2.73 (m, 5 H), (M + H)⁺ dihydrospiro[cyclohexane- 68 3.37-3.42 (m,4 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.60 (s, 1 H), 6.74 (ES⁺) at1,3′-indol]-4-yl)-1,4- (d, J = 7.5 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 1 H),10.20 (s, 1 H) 1.76 min, diazepane-1-carboxylate UV active  4-7 Isomer1: ethyl 4-(5′- 32 (400 MHz, DMSO-d₆) □: 1.19 (t, J = 7.0 Hz, 3 H),1.41-1.52 (m, F m/z 386 methyl-2′-oxo-1′,2′- and c 2 H), 1.65-1.83 (m, 8H), 2.30 (s, 3 H), 2.60-2.86 (m, 5 H), (M + H)⁺dihydrospiro[cyclohexane- 70 3.39-3.47 (m, 4 H), 4.05 (q, J = 7.0 Hz, 2H), 6.77 (d, J = 8.0 (ES⁺) at 1,3′-indol]-4-yl)-1,4- Hz, 1 H), 7.02 (d,J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 10.30 (s, 1 H) 1.69 min,diazepane-1-carboxylate UV active  4-7 Isomer 2: ethyl 4-(5′- 32 (400MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.54-1.77 (m, F m/z 386methyl-2′-oxo-1′,2′- and c 8 H), 2.07-2.16 (m, 2 H), 2.24 (s, 3 H),2.61-2.79 (m, 5 H), (M + H)⁺ dihydrospiro[cyclohexane- 70 3.37-3.42 (m,4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.67 (d, J = 7.5 (ES⁺) at1,3′-indol]-4-yl)-1,4- Hz, 1 H), 6.93 (d, J = 7.5 Hz, 1 H), 7.02 (s, 1H), 10.15 (s, 1 H) 1.73 min, diazepane-1-carboxylate UV active  4-8Isomer 1: ethyl 4-(4′- 32 (400 MHz, MeOD-d₄) □: 1.27-1.35 (m, 3 H),1.74-1.86 (m, 4 F m/z 386 methyl-2′-oxo-1′,2′- and c H), 2.30-2.47 (m, 8H), 2.78-2.97 (m, 6 H), 3.53-3.60 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 72 H), 4.15 (q, J = 7.0 Hz, 2 H), 6.70 (d, J =7.5 Hz, 1 H), 6.77 (d, J = (ES⁺) at 1,3′-indol]-4-yl)-1,4- 7.5 Hz, 1 H),7.07 (t, J = 7.5 Hz, 1 H) 1.77 min, diazepane-1-carboxylate UV active 4-8 Isomer 2: ethyl 4-(4′- 32 (400 MHz, MeOD-d₄) □: 1.27-1.36 (m, 3 H),1.84-1.93 (m, 4 F m/z 386 methyl-2′-oxo-1′,2′- and c H), 2.38-2.54 (m, 8H), 2.78-2.97 (m, 6 H), 3.54-3.61 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 72 H), 4.14-4.19 (m, 2 H), 6.68 (d, J = 8.0Hz, 1 H), 6.78 (d, J = 8.0 (ES⁺) at 1,3′-indol]-4-yl)-1,4- Hz, 1 H),7.05 (t, J = 8.0 Hz, 1 H) 1.77 min, diazepane-1-carboxylate UV active 4-9 Isomer 1: ethyl 4-(6′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0Hz, 3 H), 1.47-1.50 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and c 2 H),1.71-1.78 (m, 8 H), 2.61-2.85 (m, 5 H), 3.40-3.43 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 74 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.69 (dd, J= 2.5 Hz, 1 H), 6.74- (ES⁺) at 1,3′-indol]-4-yl)-1,4- 6.79 (m, 1 H),7.49-7.52 (m, 1 H), 10.57 (s, 1 H) 1.70 min, diazepane-1-carboxylate UVactive  4-9 Isomer 2: ethyl 4-(6′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J =7.0 Hz, 3 H), 1.54-1.80 (m, F m/z 390 fluoro-2′-oxo-1′,2′- and c 8 H),2.05-2.14 (m, 2 H), 2.60-2.77 (m, 5 H), 3.37-3.41 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 74 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.59 (dd, J= 9.0, 2.0 Hz, 1 H), 6.71- (ES⁺) at 1,3′-indol]-4-yl)-1,4- 6.76 (m, 1H), 7.23 (dd, J = 8.0, 5.5 Hz, 1 H), 10.41 (br s, 1 H) 1.72 min,diazepane-1-carboxylate UV active  4-10 Isomer 1: ethyl 4-(5′- 32 (400MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.49-1.52 (m, F m/z 390fluoro-2′-oxo-1′,2′- and c 2 H), 1.63-1.78 (m, 8 H), 2.63-2.80 (m, 5 H),3.42-3.43 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 76 H), 4.04 (q, J =7.0 Hz, 2 H), 6.87 (dd, J = 8.5, 4.5 Hz, 1 H), 7.04- (ES⁺) at1,3′-indol]-4-yl)-1,4- 7.09 (m, 1 H), 7.29-7.31 (m, 1 H), 10.45 (s, 1 H)1.68 min, diazepane-1-carboxylate UV active  4-10 Isomer 2: ethyl 4-(5′-32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.49-1.85 (m, F m/z390 fluoro-2′-oxo-1′,2′- and c 8 H), 2.04-2.17 (m, 2 H), 2.61-2.78 (m, 5H), 3.37-3.42 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 76 H), 4.04 (q, J= 7.0 Hz, 2 H), 6.76 (dd, J = 8.5, 4.5 Hz, 1 H), 6.93- (ES⁺) at1,3′-indol]-4-yl)-1,4- 6.99 (m, 1 H), 7.18 (dd, J = 2.5, 8.5 Hz, 1 H),10.28 (s, 1 H) 2.00 min, diazepane-1-carboxylate UV active  4-11 Isomer1: ethyl 4-(6′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.38-1.48 (m, F m/z 402 methoxy-2′-oxo-1′,2′- and c 2 H), 1.63-1.80 (m,8 H), 2.60-2.84 (m, 5 H), 3.40-3.51 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 78 H), 3.73 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2H), 6.45 (s, 1 H), 6.52 (d, (ES⁺) at 1,3′-indol]-4-yl)-1,4- J = 8.0 Hz,1 H), 7.39 (d, J = 8.0 Hz, 1 H), 10.38 (s, 1 H) 1.72 min,diazepane-1-carboxylate UV active  4-11 Isomer 2: ethyl 4-(6′- 32 (400MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.76 (m, F m/z 402methoxy-2′-oxo-1′,2′- and c 8 H), 2.05-2.15 (m, 2 H), 2.58-2.78 (m, 5H), 3.38-3.41 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 78 H), 3.71 (s, 3H), 4.03 (q, J = 7.0 Hz, 2 H), 6.35 (d, J = 2.5 Hz, 1 (ES⁺) at1,3′-indol]-4-yl)-1,4- H), 6.48 (dd, J = 2.5, 8.0 Hz, 1 H), 7.09 (d, J =8.0 Hz, 1 H), 1.74 min, diazepane-1-carboxylate 10.21 (s, 1 H) UV active 4-12 Isomer 1: ethyl 4-(5′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0Hz, 3 H), 1.44-1.53 (m, F m/z 402 methoxy-2′-oxo-1′,2′- and c 2 H),1.65-1.83 (m, 8 H), 2.62-2.86 (m, 5 H), 3.40-3.52 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 80 H), 3.73 (s, 3 H), 4.04 (q, J = 7.0 Hz, 2H), 6.80 (s, 2 H), 7.01 (s, (ES⁺) at 1,3′-indol]-4-yl)-1,4- 1 H), 10.27(s, 1 H) 1.70 min, diazepane-1-carboxylate UV active  4-12 Isomer 2:ethyl 4-(5′- 32 (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.53-1.80 (m, F m/z 402 methoxy-2′-oxo-1′,2′- and c 8 H), 2.08-2.16 (m,2 H), 2.64-2.73 (m, 5 H), 3.38-3.41 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 80 H), 3.69 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2H), 6.69 (s, 2 H), 6.87 (s, (ES⁺) at 1,3′-indol]-4-yl)-1,4- 1 H), 10.08(s, 1 H) 1.73 min, diazepane-1-carboxylate UV active  4-13 Isomer 2:ethyl 4-(6′- 32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.55-1.88 (m, F m/z 397 cyano-2′-oxo-1′,2′- and 8 H), 2.04-2.14 (m, 2H), 2.63-2.77 (m, 5 H), 3.39-3.48 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 110 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.13 (s, 1H), 7.42-7.47 (m, 2 H). (ES⁺) at 1,3′-indol]-4-yl)-1,4- NH not observed.1.70 min, diazepane-1-carboxylate UV active  4-14 Isomer 1: ethyl 4-(5′-32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.60 (m, Fm/z 398 cyano-2′-oxo-1′,2′- and 2 H), 1.65-1.84 (m, 8 H), 2.59-2.88 (m,5 H), 3.40-3.46 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 112 H), 4.04(q, J = 7.0 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1 H), 7.72(d, J = (ES⁺) at1,3′-indol]-4-yl)-1,4- 8.0 Hz, 1 H), 7.85 (s, 1 H), 10.95 (s, 1 H) 1.62min, diazepane-1-carboxylate UV active  4-14 Isomer 2: ethyl 4-(5′- 32 c(400 MHz, DMSO-d₆ with D₂O wash) □: 1.17 (t, J = 7.0 Hz, 3 H), F m/z 398cyano-2′-oxo-1′,2′- and 1.55-2.22 (m, 10 H), 2.65-2.94 (m, 5 H),3.34-3.51 (m, 4 H), (M + H)⁺ dihydrospiro[cyclohexane- 112 4.03 (q, J =7.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = (ES⁺) at1,3′-indol]-4-yl)-1,4- 8.0 Hz, 1 H), 7.72 (s, 1 H) 1.64 min,diazepane-1-carboxylate UV active  4-15 Isomer 2: ethyl 4-(2′-oxo- 32 c(400 MHz, DMSO-d₆ with D₂O wash) □: 1.17 (t, J = 7.0 Hz, 3 H), F m/z 3741′,2′- and 1.59-1.84 (m, 8 H), 2.01-2.14 (m, 2 H), 2.68-2.81 (m, 5 H),(M + H)⁺ dihydrospiro[cyclohexane- 90 3.36-3.46 (m, 4 H), 4.02 (q, J =7.0 Hz, 2 H), 6.94-6.97 (m, 1 (ES⁺) at 1,3′-pyrrolo[2,3- H), 7.60 (d, J= 7.0 Hz, 1 H), 8.01 (d, J = 4.5 Hz, 1 H) 1.52 min,b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-16 Isomer 1:ethyl 4-(5′- 32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.52-1.86 (m, F m/z 407 chloro-2′-oxo-1′,2′- and 8 H), 2.00-2.14 (m, 2H), 2.59-2.77 (m, 5 H), 3.37-3.42 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 93 H), 4.03 (q, J = 7.0 Hz, 2 H), 7.77 (s, 1H), 8.05 (d, J = 2.0 Hz, 1 (ES⁺) at 1,3′-pyrrolo[2,3- H). NH notobserved. 1.64 min, b]pyridin]-4-yl)-1,4- UV activediazepane-1-carboxylate  4-16 Isomer 2: ethyl 4-(5′- 32 c (400 MHz,DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.53-1.89 (m, F m/z 407chloro-2′-oxo-1′,2′- and 10 H), 2.61-2.88 (m, 5 H), 3.39-3.49 (m, 4 H),4.04 (q, J = 7.0 (M + H)⁺ dihydrospiro[cyclohexane- 93 Hz, 2 H), 7.83(d, J = 2.0 Hz, 1 H), 8.17 (d, J = 2.0 Hz, 1 H), (ES⁺) at1,3′-pyrrolo[2,3- 11.26 (s, 1 H) 1.66 min, b]pyridin]-4-yl)-1,4- UVactive diazepane-1-carboxylate  4-17 Isomer 1: ethyl 4-(5′- 32 i (400MHz, CDCl₃) □ □: 1.27 (t, J = 7.0 Hz, 3 H), 1.61-2.05 (m, O m/z 403methoxy-2′-oxo-1′,2′- and 10 H), 2.69-2.88 (m, 5 H), 3.44-3.60 (m, 4 H),3.87 (s, 3 H), (M + H)⁺ dihydrospiro[cyclohexane- 113 4.15 (q, J = 7.0Hz, 2 H), 7.39 (s, 1 H), 7.80 (s, 1 H), 9.16-9.19 (ES⁺) at1,3′-pyrrolo[2,3- (m, 1 H) 3.99 min, b]pyridin]-4-yl)-1,4- UV activediazepane-1-carboxylate  4-17 Isomer 2: ethyl 4-(5′- 32 i (400 MHz,CDDl₃) □ □: 1.26 (t, J = 7.0 Hz, 3 H), 1.61-1.95 (m, 8 O m/z 403methoxy-2′-oxo-1′,2′- and H), 2.19-2.29 (m, 2 H), 2.62-2.84 (m, 5 H),3.44-3.57 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 113 H), 3.83 (s, 3H), 4.14 (q, J = 7.0 Hz, 2 H), 7.02-7.03 (m, 1 H), (ES⁺) at1,3′-pyrrolo[2,3- 7.74-7.76 (m, 1 H), 8.32-8.36 (m, 1 H) 4.02 min,b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-18 Isomer 2:ethyl 4-(1′,2′- 32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H),1.31-1.40 (m, G m/z 359 dihydrospiro[cyclohexane- and 2 H), 1.52-1.72(m, 8 H), 2.54-2.73 (m, 5 H), 3.30 (s, 2 H), (M + H)⁺ 1,3′-pyrrolo[2,3-116 3.35-3.40 (m, 4 H), 4.03 (q, J = 7.0 Hz, 2 H), 6.35 (s, 1 H), 6.39-(ES⁺) at b]pyridin]-4-yl)-1,4- 6.42 (m, 1 H), 7.16-7.18 (m, 1 H), 7.68(dd, J = 5.0, 1.5 Hz, 1 H) 5.25 min, diazepane-1-carboxylate UV active 4-19 Isomer 1: ethyl 4-[1′- 32 c (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0Hz, 3 H), 1.31-1.51 (m, G m/z 437 (methylsulfonyl)-1′,2′- and 2 H),1.60-1.84 (m, 8 H), 2.58-2.84 (m, 5 H), 3.31 (s, 3 H), (M + H)⁺dihydrospiro[cyclohexane- 117 3.39-3.48 (m, 4 H), 3.84 (s, 2 H), 4.03(q, J = 7.0 Hz, 2 H), 7.00- (ES⁺) at 1,3′-pyrrolo[2,3- 7.03 (m, 1 H),7.63-7.65 (m, 1 H), 8.11-8.12 (m, 1 H) 5.39 min, b]pyridin]-4-yl]-1,4-UV active diazepane-1-carboxylate  4-19 Isomer 2: ethyl 4-[1′- 32 c (400MHz, MeOD-d₄) □: 1.29 (t, J = 7.0 Hz, 3 H), 1.51-1.60 (m, G m/z 437(methylsulfonyl)-1′,2′- and 2 H), 1.76-1.96 (m, 8 H), 2.78-3.03 (m, 5H), 3.28 (s, 3 H), (M + H)⁺ dihydrospiro[cyclohexane- 117 3.52-3.65 (m,4 H), 3.95 (s, 2 H), 4.16 (q, J = 7.0 Hz, 2 H), 7.01- (ES⁺) at1,3′-pyrrolo[2,3- 7.04 (m, 1 H), 7.61-7.63 (m, 1 H), 8.10 (dd, J = 1.0,5.0 Hz, 1 H) 5.49 min, b]pyridin]-4-yl]-1,4- UV activediazepane-1-carboxylate  4-20 Isomer 2: ethyl 4-(2′-oxo- 32 c (400 MHz,MeOD-d₄) □: 1.29 (t, J = 7.0 Hz, 3 H), 1.76-1.97 (m, G m/z 373 1′,2′-and 8 H), 2.23-2.33 (m, 2 H), 2.79-2.91 (m, 5 H), 3.50-3.61 (m, 4 (M +H)⁺ dihydrospiro[cyclohexane- 118 H), 4.15 (q, J = 7.0 Hz, 2 H), 7.36(d, J = 5.0 Hz, 1 H), 8.12 (s, 1 (ES⁺) at 1,3′-pyrrolo[2,3- H), 8.25 (d,J = 5.0 Hz, 1 H) 4.55 min, c]pyridin]-4-yl)-1,4- UV activediazepane-1-carboxylate  4-21 Isomer 1: ethyl 4-(5′- 32 i (400 MHz,CDCl₃) □ □: 1.26 (t, J = 7.0 Hz, 3 H), 1.54-1.98 (m, 8 O m/z 403methoxy-2′-oxo-1′,2′- and H), 2.15-2.29 (m, 2 H), 2.63-2.87 (m, 5 H),3.45-3.57 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 95 H), 3.89 (s, 3 H),4.14 (q, J = 7.0 Hz, 2 H), 6.56 (s, 1 H), 7.33 (s, (ES⁺) at1,3′-pyrrolo[2,3- 1 H), 7.67 (s, 1 H) 3.96 min, c]pyridin]-4-yl)-1,4- UVactive diazepane-1-carboxylate  4-22 Isomer 2: ethyl 4-(2′-oxo- 32 c(400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.57-1.86 (m, F m/z 3731′,2′- and 8 H), 2.00-2.12 (m, 2 H), 2.60-2.79 (m, 5 H), 3.38-3.42 (m, 4(M + H)⁺ dihydrospiro[cyclohexane- 99 H), 4.04 (q, J = 7.0 Hz, 2 H),7.13-7.14 (m, 2 H), 8.07-8.08 (m, (ES⁺) at 1,3′-pyrrolo[3,2- 1 H), 10.48(s, 1 H) 1.53 min, b]pyridin]-4-yl)-1,4- UV activediazepane-1-carboxylate  4-23 Isomer 1: ethyl 4-(5′- 32 c (400 MHz,DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.60-1.87 (m, F m/z 388methyl-2′-oxo-1′,2′- and 8 H), 2.00-2.13 (m, 2 H), 2.39 (s, 3 H),2.64-2.82 (m, 5 H), (M + H)⁺ dihydrospiro[cyclohexane- 120 3.39-3.44 (m,4 H), 4.04 (q, J = 7.0 Hz, 2 H), 6.99 (d, J = 8.0 (ES⁺) at1,3′-pyrrolo+3,2- Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 10.35 (s, 1 H)1.57 min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  4-24Isomer 1: ethyl 4-(5′- 32 c (400 MHz, DMSO-d₆) □: 1.17 (t, J = 7.0 Hz, 3H), 1.53-1.76 (m, G m/z 403 methoxy-2′-oxo-1′,2′- and 8 H), 2.21-2.36(m, 2 H), 2.68-2.80 (m, 5 H), 3.39-3.51 (m, 4 (M + H)⁺dihydrospiro[cyclohexane- 97 H), 3.83 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2H), 6.67 (d, J = 8.5 Hz, 1 (ES⁺) at 1,3′-pyrrolo[3,2- H), 7.23 (d, J =8.5 Hz, 1 H), 10.30 (s, 1 H) 5.48 min, b]pyridin]-4-yl)-1,4- UV activediazepane-1-carboxylate  4-24 Isomer 2: ethyl 4-(5′- 32 c (400 MHz,DMSO-d₆) □: 1.18 (t, J = 7.0 Hz, 3 H), 1.68-1.78 (m, G m/z 403methoxy-2′-oxo-1′,2′- and 8 H), 2.00-2.13 (m, 2 H), 2.61-2.81 (m, 5 H),3.38-3.47 (m, 4 (M + H)⁺ dihydrospiro[cyclohexane- 97 H), 3.80 (s, 3 H),4.04 (q, J = 7.0 Hz, 2 H), 6.60 (d, J = 8.5 Hz, 1 (ES⁺) at1,3′-pyrrolo[3,2- H), 7.16 (d, J = 8.5 Hz, 1 H), 10.20 (s, 1 H) 5.61min, b]pyridin]-4-yl)-1,4- UV active diazepane-1-carboxylate  5-1 Isomer2: ethyl 4-[4-(4- 31 f (400 MHz, DMSO-d₆) δ: 0.91-1.23 (m, 7 H),1.45-1.68 (m, 7 H), B m/z 363 ethyl-5-methyl-1 H- 1.90-2.10 (m, 5 H),2.28-2.49 (m, 3 H), 2.57-2.62 (m, 2 H), (M + H)⁺imidazol-2-yl)cyclohexyl]- 2.64-2.75 (m, 3 H), 3.38-3.43 (m, 4 H), 4.01(q, J = 6.8 Hz, 2 (ES⁺), at 1,4-diazepane-1- H), 10.97 (br. s, 1 H) 3.22min, carboxylate UV active  6-1 Isomer 2: ethyl [1-(4- 1, 12 b (400 MHz,DMSO-d₆) □: 1.17 (t, J = 7.2 Hz, 3 H), 1.45-1.80 (m, B m/z 370cyano-4-phenylcyclohexyl) and 7 H), 1.81-1.99 (m, 5 H), 2.24-2.40 (m, 3H), 2.70 (s, 3 H), (M + H)⁺ piperidin-4-yl] 55 2.95-3.10 (m, 2 H),3.68-3.85 (m, 1 H), 4.02 (q, J = 7.2 Hz, 2 (ES⁺), at methylcarbamate H),7.32-7.41 (m, 1 H), 7.41-7.49 (m, 2 H) and 7.50-7.57 (m, 4.57 min, 2 H).UV active  6-2 Isomer 2: ethyl 1{1-(4- 2, 12 b (400 MHz, DMSO-d6) □:1.05-1.11 (m, 2 H), 1.14 (t, J = 7.0 Hz, B m/z 370 1′,2′ cyano-4- and 3H), 1.24-1.32 (m, 1 H), 1.59-1.92 (m, 10 H), 2.23-2.30 (m, (M + H)⁺phenylcyclohexyl)piperidin- 55 3 H), 2.82-2.85 (m, 2 H), 2.91-2.96 (m, 2H), 3.96 (q, J = 7.0 (ES⁺), at 4-yl]methyl}carbamate Hz, 2 H), 7.11 (br.s, 1 H), 7.35-7.39 (m, 1 H), 7.44-7.48 (m, 2 4.17 min, H) and 7.51-7.54(m, 2 H). UV active  7-1 Isomer 1: ethyl [1-(2′-oxo- 65 c (400 MHz,MeOD-d₄) □: 1.26 (t, J = 7.0 Hz, 3 H), 1.72-2.25 (m, F m/z 372 1′,2′-and 12 H), 3.13-3.26 (m, 2 H), 3.35-3.42 (m, 1 H), 3.59-3.78 (m, (M +H)⁺ dihydrospiro[cyclohexane- 101 3 H), 4.08-4.13 (m, 2 H), 7.00 (d, J =7.5 Hz, 1 H), 7.08 (t, J = (ES⁺) at 1,3′-indol]-4-Apiperidin- 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 1.61 min,4-yl]carbamate 8.54 (br s, 1 H) UV active  7-1 Isomer 2: ethyl[1-(2′-oxo- 65 c (400 MHz, MeOD-d₄) □: 1.26 (t, J = 7.0 Hz, 3 H),1.76-2.20 (m, F m/z 372 1′,2′- and 10 H), 2.48-2.57 (m, 2 H), 3.20-3.26(m, 2 H), 3.37-3.54 (m, (M + H)⁺ dihydrospiro[cyclohexane- 101 3 H),3.67-3.80 (m, 1 H), 4.08-4.13 (m, 2 H), 6.90 (d, J = 7.5 (ES⁺) at1,3′-indol]-4-yl)piperidin- Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H),7.20-7.23 (m, 2 H), 8.56 (br 1.64 min, 4-yl]carbamate s, 1 H) UV active 7-2 Isomer 1: ethyl 1[1-(2′- 55 h (400 MHz, MeOD-d₄) □: 1.22-1.39 (m, 5H), 1.49-1.67 (m, 3 F m/z 386 oxo-1′,2′- and H), 1.80-2.06 (m, 8 H),2.34-2.39 (m, 2 H), 2.55-2.64 (m, 1 (M + H)⁺ dihydrospiro[cyclohexane-103 H), 3.03 (d, J = 6.5 Hz, 2 H), 3.15-3.18 (m, 2 H), 4.06-4.17 (m,(ES⁺) at 1,3′-indol]-4-yl)piperidin- 2 H), 6.97 (d, J = 7.5 Hz, 1 H),7.05 (t, J = 7.5 Hz, 1 H), 7.26 (t, J = 1.63 min, 4-yl]methyl}carbamate7.5 Hz, 1 H), 7.63 (d, J = 7.5 Hz, 1 H) UV active  7-2 Isomer 2: ethyl1[1-(2′- 55 h (400 MHz, DMSO-d₆) □: 1.05-1.39 (m, 6 H), 1.59-1.78 (m, 9F m/z 386 oxo-1′,2′- and H), 2.09-2.24 (m, 4 H), 2.84-2.89 (m, 4 H),3.97 (q, J = 7.0 Hz, (M + H)⁺ dihydrospiro[cyclohexane- 103 2 H), 6.79(d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 7.10- (ES⁺) at1,3′-indol]-4-yl)piperidin- 7.15 (m, 2 H), 7.22 (d, J = 7.0 Hz, 1 H),10.23 (s, 1 H) 1.67 min, 4-yl]methyl}carbamate UV active  8-1 Mixture ofisomers: ethyl 3 a (400 MHz, DMSO-d₆) □: 1.17 (t, J = 7.1 Hz, 3 H),1.54-1.73(m, B m/z 370 5-(4-cyano-4- and 6 H), 1.82-2.01 (m, 5 H),2.03-2.30 (m, 3 H), 2.54-2.66 (m, 4 (M + H)⁺ phenylcyclohexyl)-1,5- 12H), 2.95-3.10 (m, 2 H), 3.68-3.85 (m, 1 H), 4.03 (q, J = 7.1 Hz, (ES⁺),at diazocane-1-carboxylate 2 H), 7.32-7.39 (m, 1 H), 7.40-7.47 (m, 2 H)and 7.50-7.57 5.07 min, (m, 2 H). UV active  9-1 Isomer 1: ethyl 2-(4-4, 12 b (400 MHz, DMSO-d₆) □: 1.14 (t, J = 6.9 Hz, 3 H), 1.19-1.36 (m, Bm/z 368 cyano-4- and 2 H), 1.75-1.89 (m, 4 H), 1.89-1.98 (m, 2 H),2.01-2.11 (m, 3 (M + H)⁺ phenylcyclohexyl)-2,6- 55 H), 2.98-3.11 (m, 4H), 3.20-3.35 (m, 4 H), 3.97 (q, J = 6.9 Hz, (ES⁺), atdiazaspiro[3.4]octane-6- 2 H), 7.29-7.35 (m, 1 H), 7.36-7.43 (m, 2 H)and 7.45-7.55 3.96 min, carboxylate (m, 2 H). UV active  9-1 Isomer 2:ethyl 2-(4- 4, 12 b (400 MHz, DMSO-d₆) □: 1.17 (t, J = 7.0 Hz, 3 H),1.63-1.73 (m, B m/z 368 cyano-4- and 4 H), 1.76-1.85 (m, 2 H), 1.85-2.09(m, 2 H), 2.11-2.26 (m, 2 (M + H)⁺ phenylcyclohexyl)-2,6- 55 H),2.38-2.49 (m, 1 H), 2.99-3.10 (m, 4 H), 3.22-3.43 (m, 4 (ES⁺), atdiazaspiro[3.4]octane-6- H), 4.01 (q, J = 7.0 Hz, 2 H), 7.34-7.40 (m, 1H) and 7.41-7.55 4.59 min, carboxylate (m, 4 H). UV active 10-1 Mixtureof isomers: ethyl 65 j (400 MHz, DMSO-d₆) □: 1.53 (t, J = 7.0 Hz, 3 H),1.55-2.32 (m, B m/z 384 6-(2′-oxo-1′,2′- and 10 H), 2.55-2.88 (m, 5 H),3.74-3.90 (m, 4 H), 3.99 (q, J = 7.0 (M + H)⁺ dihydrospiro[cyclohexane-122 Hz, 2 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.91-6.95 (m, 1 H), 7.14 (td,(ES⁺) at 1,3′-indol]-4-yl)-2,6- J = 7.5, 1.0 Hz, 1 H), 7.29 (d, J = 7.5Hz, 1 H), 10.22 (s, 1 H) 3.74 min, diazaspiro[3.4]octane-2- UV activecarboxylate 11-1 Isomer 2: ethyl 7-(4- 5, 12 b (400 MHz, CDCl₃) □: 1.24(t, J = 7.2 Hz, 3 H), 1.48-1.59 (m, 3 B m/z 382 cyano-4- and H),1.67-2.06 (m, 8 H), 2.20-2.51 (m, 4 H), 2.53-2.67 (m, 1 (M + H)⁺phenylcyclohexyl)-2,7- 55 H), 2.69-2.84 (m, 1 H), 2.89-3.02 (m, 1 H),3.44-3.56 (m, 1 (ES⁺), at diazaspiro[3.5]nonane-2- H), 3.63-3.76 (m, 2H), 4.10 (q, J = 7.2 Hz, 2 H) and 7.27-7.70 4.45 min, carboxylate (m, 5H). UV active 12-1 Isomer 1: ethyl 8-(2′-oxo- 6 k (400 MHz, CDCl₃) E □:1.15-1.23 (m, 3 H), 1.39-2.10 (m, 11 H), B m/z 412 1′,2′- and 2.28-2.80(m, 6 H), 3.06-3.46 (m, 6 H), 4.03-4.11 (m, 2 H), (M + H)⁺dihydrospiro[cyclohexane- 65 6.76-7.17 (m, 3 H), 7.39-7.72 (m, 2 H)(ES⁺) at 1,3′-indol]-4-yl)-2,8- 3.58 min, diazaspiro[4.5]decane-2- UVactive carboxylate 12-2 Isomer 1: ethyl 4-[2- Ex h (400 MHz, CDCl₃) □ □:1.17-1.22 (m, 3 H), 1.39 (t, J = 9.5 Hz, 3 B m/z 484(ethoxycarbonyl)-2,8- 12-1 H), 1.47-2.18 (m, 16 H), 2.46-2.70 (m, 1 H),3.07-3.42 (m, 5 (M + H)⁺ diazaspiro[4.5]dec-8-yl]- and H), 3.79-3.87 (m,1 H), 4.07 (q, J = 9.5 Hz, 2 H), 4.41 (q, J = 9.5 (ES⁺) at2′-oxospiro[cyclohexane- 55 Hz, 2 H), 7.06-7.16 (m, 2 H), 7.25-7.30 (m,1 H), 7.89 (d, J = 4.54 min, 1,3′-indole]-1′(2′ H)- 11.0 Hz, 1 H) UVactive carboxylate 13-1 Isomer 2: ethyl 8-(4- 6 and a (400 MHz, CDCl₃)□: 1.26 (t, J = 7.2 Hz, 3 H), 1.50-1.62 (m, 5 B m/z 396 cyano-4- 12 H),1.63-1.77 (m, 2 H), 1.81-2.06 (m, 6 H), 2.24-2.38 (m, 4 (M + H)⁺phenylcyclohexyl)-2,8- H), 2.45-2.60 (m, 2 H), 3.13-3.25 (m, 2 H),3.34-3.48 (m, 2 (ES⁺), at diazaspiro[4.5]decane-2- H), 4.13 (q, J = 7.2Hz, 2 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.40 (d, J = 4.71 min, carboxylate7.6 Hz, 2 H) and 7.51 (d, J = 7.6 Hz, 2 H). UV active 14-1 Isomer 1:ethyl 7-(4- 7 and a (400 MHz, DMSO-d₆) □: 1.19 (t, J = 6.8 Hz, 3 H),1.26-1.42 (m, B m/z 368 cyano-4- 12 1 H), 1.52-1.69 (m, 2 H), 1.80-2.00(m, 6 H), 2.04-2.12 (m, 2 (M + H)⁺ phenylcyclohexyl)-3,7- H), 2.18-2.27(m, 1 H), 2.38 (t, J = 7.0 Hz, 1 H), 2.91 (t, J = 7.2 (ES⁺), atdiazabicyclo[4.2.0]octane- Hz, 1 H), 3.00 (d, J = 6.0 Hz, 1 H),3.30-3.39 (m, 2 H), 3.47- 4.31 min, 3-carboxylate 3.60 (m, 1 H),3.81-3.89 (m, 1 H), 4.04 (q, J = 6.8 Hz, 2 H), 7.33- UV active 7.38 (m,1 H), 7.40-7.47 (m, 2 H) and 7.50-7.56 (m, 2 H). 14-2 Isomer 2: ethyl7-(4- 7 and a (400 MHz, DMSO-d₆) □: 1.08-1.22 (m, 3 H), 1.59-1.85 (m, 8B m/z 368 cyano-4- 12 H), 2.04-2.27 (m, 2 H), 2.30-2.44 (m, 1 H), 2.87(t, J = 6.8 Hz, (M + H)⁺ phenylcyclohexyl)-3,7- 1 H), 3.01 (dd, J = 7.0and 2.3, 1 H), 3.37-3.41 (m, 1 H), 3.42- (ES⁺), atdiazabicyclo[4.2.0]octane- 3.77 (m, 5 H), 4.03 (q, J = 7.0 Hz, 2 H),7.33-7.42 (m, 1 H) and 5.01 min, 3-carboxylate 7.40-7.58 (m, 4 H). UVactive 15-1 Isomer 2: ethyl 5-(4- 8 and a (400 MHz, DMSO-d₆) □:1.08-1.24 (m, 3 H), 1.62-1.99 (m, 7 B m/z 368 cyano-4- 12 H), 2.01-2.43(m, 5 H), 2.55-2.97 (m, 4 H), 3.12-3.29 (m, 1 (M + H)⁺phenylcyclohexyl)hexahy H), 3.42-3.59 (m, 1 H), 3.91-4.06 (m, 2 H),4.07-4.22 (m, 1 (ES⁺), at dropyrrolo[3,4-b]pyrrole- H), 7.28-7.39 (m, 1H) and 7.40-7.56 (m, 4 H). 4.92 min, 1(2 H)-carboxylate UV active 16-1Isomer 1: ethyl 1-(4- 9, 12 b (400 MHz, DMSO-d₆) □: 1.18 (t, J = 7.2 Hz,3 H), 1.42-1.68 (m, B m/z 368 cyano-4- and 4 H), 1.87-2.19 (m, 8 H),2.41-2.56 (m, 2 H), 2.64-2.79 (m, 2 (M + H)⁺ phenylcyclohexyl)hexahy 55H), 2.96-3.06 (m, 1 H), 3.21-3.41 (m, 2 H), 4.02 (q, J = 7.2 Hz, (ES⁺),at dropyrrolo[3,4-b]pyrrole- 2 H), 7.33-7.39 (m, 1 H), 7.41-7.49 (m, 2H) and 7.50-7.58 4.10 min, 5(1 H)-carboxylate (m, 2 H). UV active 16-1Isomer 2: ethyl 1-(4- 9, 12 b (400 MHz, DMSO-d₆) □: 0.96-1.13 (m, 3 H),1.32-1.48 (m, 2 B m/z 368 cyano-4- and H), 1.63-1.96 (m, 8 H), 2.07-2.23(m, 2 H), 2.37 (td, J = 9.1 (M + H)⁺ phenylcyclohexyl)hexahy 55 and6.15, 1 H), 2.41-2.52 (m, 2 H), 2.59-2.71 (m, 1 H), 2.76- (ES⁺), atdropyrrolo[3,4-b]pyrrole- 2.84 (m, 1 H), 3.14-3.33 (m, 2 H), 3.92 (q, J= 7.0 Hz, 2 H), 7.27- 4.60 min, 5(1H)-carboxylate 7.33 (m, 1 H),7.35-7.42 (m, 2 H) and 7.42-7.49 (m, 2 H). UV active 17-1 Isomer 2:ethyl 3-(4- 10, 12 b (400 MHz, DMSO-d₆) □: 1.00-1.12 (m, 3 H), 1.15-1.25(m, 2 B m/z 368 cyano-4- and H), 1.48-1.77 (m, 3 H), 1.77-1.94 (m, 4 H),2.03-2.12 (m, 1 (M + H)⁺ phenylcyclohexyl)-3,7- 55 H), 2.13-2.28 (m, 2H), 2.31-2.56 (m, 3 H), 2.70 (dd, J = 12 (ES⁺), atdiazabicyclo[4.2.0]octane- and 5.7, 1 H), 3.40-3.49 (m, 1 H), 3.69-3.82(m, 1 H), 3.84- 4.43 min, 7-carboxylate 4.02 (m, 2 H), 4.14-4.25 (m, 1H), 7.25-7.33 (m, 1 H), 7.34- UV active 7.41 (m, 2 H) and 7.42-7.51 (m,2 H). 18-1 Isomer 1: ethyl 11 a (400 MHz, DMSO-d₆) □: 1.12-1.21 (m, 3H), 1.22-1.68 (m, 7 B m/z 382 (4aS,7aS)-1-(4-cyano-4- and H), 1.71-1.84(m, 2 H), 1.86-2.26 (m, 6 H), 2.58-2.74 (m, 1 (M + H)⁺phenylcyclohexyl)octahy 12 H), 3.07-3.31 (m, 3 H), 3.36-3.59 (m, 2 H),3.95-4.09 (m, 2 (ES⁺), at dro-6H-pyrrolo[3,4- H), 7.32-7.40 (m, 1 H),7.40-7.48 (m, 2 H) and 7.51-7.58 (m, 4.39 min, b]pyridine-6-carboxylate2 H). UV active 19-1 Isomer 2: 4-{[(1R,3S)-3- 26 l (400 MHz, CDCl₃) □:1.55-1.66 (m, 2 H), 1.69-1.81 (m, 2 H), E m/z 352 (3-methyl-1,2,4- and1.88-2.16 (m, 8 H), 2.37 (s, 3 H), 2.38-2.55 (m, 3 H), 2.97- (M + H)⁺oxadiazol-5-yl) 126 3.06 (m, 1 H), 3.25-3.40 (m, 2 H), 7.21-7.27 (m, 1H), 7.53- (ES⁺), at cyclopentyl]amino}-1- 7.61 (m, 1 H), 7.73 (t, J =7.4 Hz, 1 H), 8.62 (d, J = 5.1 Hz, 1 H). 3.58 min, (pyridin-2-yl) UVactive. cyclohexanecarbonitrile 19-2 Isomer 2: 4-{[(1R,3S)-3- 12 l (400MHz, CDCl₃) □: 1.32 (t, J = 7.4 Hz, 3 H), 1.55-1.66 (m, 1 E m/z 365(3-ethyl-1,2,4-oxadiazol- and H), 1.70-1.82 (m, 3 H), 1.84-1.93 (m, 3H), 1.97-2.17 (m, 5 (M + H)⁺ 5-yl)cyclopentyl]amino}- 128 H), 2.24-2.35(m, 2 H), 2.38-2.49 (m, 1 H), 2.74 (q, J = 7.7 Hz, (ES), at1-phenylcyclo 2 H), 3.02-3.08 (m, 1 H), 3.24-3.42 (m, 2 H), 7.29-7.35(m, 1 5.02 min, hexanecarbonitrile H), 7.40 (t, J = 7.8 Hz, 2 H),7.47-7.54 (m, 2 H). UV active. 20-1 Isomer 2: 1-phenyl-4-{6- 12 l (400MHz, CDCl₃) □: 1.68-1.76 (m, 2 H), 1.78-1.93 (m, 4 H), E m/z 417[3-(trifluoromethyl)-1,2,4- and 2.20-2.31 (m, 2 H), 2.33-2.40 (m, 1 H),2.57-2.74 (m, 4 H), (ES⁺), at oxadiazol-5-yl]-2- 131 3.16 (s, 2 H), 3.25(s, 2 H), 3.67-3.80 (m, 1 H), 7.28-7.34 (m, 1 (M + H)⁺azaspiro[3.3]hept-2-yl} H), 7.40 (t, J = 7.8 Hz, 2 H), 7.52 (d, J = 7.0Hz, 2 H). 5.90 min, cyclohexanecarbonitrile UV active 21-1 Isomer 3:4-[2-(3-methyl- 12 l (400 MHz, CDCl₃) □: 1.82-1.90 (m, 2 H), 1.91-1.97(m, 4 H), E m/z 377 1,2,4-oxadiazol-5-yl)-6- and 2.00-2.06 (m, 2 H),2.24-2.37 (m, 3 H), 2.38 (s, 3 H), 2.40- (M + H)⁺azaspiro[3.4]oct-6-yl]-1- 133 2.52 (m, 4 H), 2.59-2.67 (m, 4 H),3.62-3.73 (m, 1 H), 7.28- (ES⁺), at phenylcyclohexanecarbonitrile 7.34(m, 1 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.50 (d, J = 7.0 Hz, 2 H). 5.31min, UV active 21-2 Isomer 3: 1-(2- 19 l (400 MHz, CDCl₃) □: 1.90-2.05(m, 7 H), 2.33-2.51 (m, 8 H), E m/z 395 fluorophenyl)-4-[2-(3- and 2.38(d, J = 1.2 Hz, 3 H), 2.58-2.68 (m, 4 H), 3.60-3.71 (m, 1 (M + H)⁺methyl-1,2,4-oxadiazol-5- 133 H), 7.06-7.19 (m, 2 H), 7.28-7.35 (m, 1H), 7.46 (t, J = 7.8 Hz, (ES⁺), at yl)-6-azaspiro[3.4]oct-6- 1 H). 5.35min, yl]cyclohexanecarbonitrile UV active 21-3 Isomer 3: 1-(5- 27 c (400MHz, MeOD-d₄) □: 1.70-1.84 (m, 2 H), 1.85-2.10 (m, 5 R m/z 396fluoropyridin-2-yl)-4-[2-(3- and H), 2.28-2.36 (m, 4 H), 2.38-2.46 (m, 4H), 2.51-2.61 (m, 3 (M + H)⁺ methyl-1,2,4-oxadiazol-5- 133 H), 2.63-2.71(m, 4 H), 3.65-3.75 (m, 1 H), 7.61-7.75 (m, 2 (ES⁺), atyl)-6-azaspiro[3.4]oct-6-yl] H), 8.47-8.57 (m, 1 H). 4.23 min,cyclohexanecarbonitrile UV active 21-3 Isomer 4: 1-(5- 27 c (400 MHz,MeOD-d₄) □: 1.77-2.02 (m, 7 H), 2.31-2.45 (m, 6 R m/z 396fluoropyridin-2-yl)-4-[2-(3- and H), 2.45-2.54 (m, 3 H), 2.54-2.64 (m, 4H), 2.78 (s, 2 H), 3.65- (M + H)⁺ methyl-1,2,4-oxadiazol-5- 133 3.75 (m,1 H), 7.61-7.73 (m, 2 H), 8.50 (d, J = 2.8 Hz, 1 H). (ES⁺), atyl)-6-azaspiro[3.4]oct-6-yl] 4.43 min, cyclohexanecarbonitrile UV active21-4 Isomer 4: 1-(5- 44 c (400 MHz, MeOD-d₄) □: 1.75-2.01 (m, 10 H),2.30-2.45 (m, 5 R m/z 408 methoxypyridin-2-yl)-4- and H), 2.54-2.65 (m,5 H), 2.78 (s, 2 H), 3.63-3.72 (m, 1 H), 3.88 (M + H)⁺[2-(3-methyl-1,2,4- 133 (s, 3 H), 7.42 (dd, J = 8.8, 3.0 Hz, 1 H), 7.55(d, J = 8.8 Hz, 1 H), (ES⁺), at oxadiazol-5-yl)-6- 8.26 (d, J = 3.0 Hz,1 H). 4.25 min, azaspiro[3.4]oct-6-yl] UV active cyclohexanecarbonitrile21-5 Isomer 1: 4-[2-(3-methyl- 43 c (400 MHz, MeOD-d₄) □: 1.32 (s, 2 H),1.66-1.82 (m, 3 H), 1.97 R m/z 392 1,2,4-oxadiazol-5-yl)-6- and (dd, J =13.3, 3.0 Hz, 2 H), 2.05-2.26 (m, 10 H), 2.34-2.50 (m, (M + H)⁺azaspiro[3.4]oct-6-yl]-1- 133 5 H), 2.68-2.78 (m, 1 H), 3.12 (s, 2 H),3.63-3.77 (m, 1 H), (ES⁺), at (5-methylpyridin-2-yl) 7.40 (d, J = 8.1Hz, 1 H), 7.57 (dd, J = 8.0, 2.3 Hz, 1 H), 8.29 (d, 3.50 min,cyclohexanecarbonitrile J = 2.2 Hz, 1 H). UV active 21-5 Isomer 2:4-[2-(3-methyl- 43 c (400 MHz, MeOD-d₄) □: 1.81 (dt, J = 13.7, 10.2 Hz,2 H), 2.00 (t, R m/z 392 1,2,4-oxadiazol-5-yl)-6- and J = 7.2 Hz, 2 H),2.09 (td, J = 13.9, 3.6 Hz, 2 H), 2.19-2.29 (m, (M + H)⁺azaspiro[3.4]oct-6-yl]-1- 133 5 H), 2.34 (s, 3 H), 2.36 (s, 3 H),2.40-2.50 (m, 2 H), 2.54- (ES⁺), at (5-methylpyridin-2-yl) 2.64 (m, 2H), 2.85 (t, J = 7.2 Hz, 2 H), 3.06 (s, 2 H), 3.65-3.79 3.60 min,cyclohexanecarbonitrile (m, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.69 (dd, J= 8.1, 2.3 Hz, 1 UV active H), 8.41 (d, J = 2.2 Hz, 1 H). 22-1 Isomer 1:4-[(3R)-3-(3- 65 l (400 MHz, CDCl₃) □: 1.59-1.98 (m, 9 H), 2.12-2.22 (m,1 H), E m/z 367 methyl-1,2,4-oxadiazol-5- and 2.28-2.38 (m, 2 H), 2.40(s, 3 H), 2.42-2.54 (m, 1 H), 2.60- (M + H)⁺ yl)piperidin-1- 135 2.82(m, 2 H), 2.96-3.12 (m, 1 H), 3.20-3.39 (m, 2 H), 6.85 (d, (ES⁺), atyl]spiro[cyclohexane-1,3′- J = 7.4 Hz, 1 H), 7.03 (t, J = 8.2 Hz, 1 H),7.09-7.23 (m, 2 H), 3.95 min, indol]-2′(1′H)-one 7.78 (s, 1 H). UVactive 22-2 Isomer 1: 5′-methoxy-4- 80 c (400 MHz, MeOD-d₄) □: 1.59-1.80(m, 4 H), 1.87-2.06 (m, 7 I m/z 397 [(3R)-3-(3-methyl-1 ,2,4- and H),2.11-2.20 (m, 1 H), 2.36 (s, 3 H), 2.44-2.52 (m, 1 H), 2.59- (M + H)⁺oxadiazol-5-yl)piperidin- 135 2.75 (m, 2 H), 3.02-3.10 (m, 1 H),3.19-3.27 (m, 1 H), 3.33- (ES⁺), at 1-yl]spiro+cyclohexane- 3.39 (m, 1H), 3.79 (s, 3 H), 6.78-6.91 (m, 2 H), 7.14-7.21 (m, 4.87 min,1,3′-indol]-2′(1′1-1)-one 1 H). One exchangeable proton not observed. UVactive 22-3 Isomer 1: 5′-methyl-4- 70 c (400 MHz, MeOD-d₄) □: 1 .61 (d,J = 8.9 Hz, 2 H), 1.70-1.80 R m/z 381 [(3R)-3-(3-methyl-1 ,2,4- and (m,2 H), 1.87-1.94 (m, 6 H), 2.00-2.10 (m, 2 H), 2.16 (d, J = (M + H)⁺oxadiazol-5-yl)piperidin- 135 7.5 Hz, 1 H), 2.34 (s, 3 H), 2.36 (s, 3H), 2.42-2.52 (m, 1 H), (ES⁺), at 1-yl]spiro[cyclohexane- 2.58-2.76 (m,2 H), 3.0-3.42 (m, 2 H), 6.83 (d, J = 7.9 Hz, 1 3.57 min,1,3′-indol]-2′(1′ H)-one H), 7.06 (d, J = 8.2 Hz, 1 H), 7.43 (s, 1 H).NH not observed. UV active 22-4 Isomer 1: 6′-methyl-4- 68 c (400 MHz,MeOD-d₄) □: .59 (d, J = 8.4 Hz, 2 H), 1.65-1.79 R m/z 381[(3R)-3-(3-methyl-1,2,4- and (m, 2 H), 1.80-2.03 (m, 7 H), 2.10-2.20 (m,1 H), 2.33 (s, 3 (M + H)⁺ oxadiazol-5-yl)piperidin- 135 H), 2.36 (s, 3H), 2.49 (t, J = 10.5 Hz, 1 H), 2.60-2.76 (m, 2 H), (ES⁺), at1-yl]spiro+cyclohexane- 3.05 (d, J = 11.4 Hz, 1 H), 3.18-3.38 (m, 2 H),6.78 (s, 1 H), 3.61 min, 1,3′-indol]-2′(1′ H)-one 6.86 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1 H). NH not UV active observed. 23-1 Isomer 1:4-({[2-(3- 65 l (400 MHz, CDCl₃) □: 1.14-1.21 (m, 1 H), 1.43-1.49 (m, 1H), E m/z 353 methyl-1,2,4-oxadiazol-5- and 1.64-1.74 (m, 3 H),1.81-1.90 (m, 1 H), 1.91-1.98 (m, 2 H), (M + H)⁺yl)cyclopropyl]methyl}amino) 137 1.98-2.11 (m, 4 H), 2.34 (s, 3 H),2.72-2.87 (m, 4 H), 6.93 (d, J = (ES⁺), at spiro[cyclohexane- 7.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 3.12 min,1,3′-indol]-2′(1′H)-one 7.58 (d, J = 7.8 Hz, 1 H), 7.98-8.23 (m, 1 H).UV active 24-1 Isomer 1: 4-({(1R,3S)-3- 65 l (400 MHz, CDCl₃) □:1.54-1.77 (m, 5 H), 1.85-2.15 (m, 7 H), E m/z 421[3-(trifluoromethyl)-1,2,4- and 2.17-2.34 (m, 2 H), 2.34-2.57 (m, 1 H),2.75-2.88 (m, 1 H), (M + H)⁺ oxadiazol-5-yl] 138 3.45-3.57 (m, 1 H),3.58-3.78 (m, 1 H), 6.93-6.98 (m, 1 H), (ES⁺), atcyclopentyl}amino)spiro 6.98-7.04 (m, 1 H), 7.24 (t, J = 7.8 Hz, 1 H),7.52-7.65 (m, 1 4.42 min, [cyclohexane-1,3′- H), 8.52 (br. s., 1 H). UVactive indol]-2′(1′H)-one 24-2 Isomer 1: 5′-methyl-4- 70 l (400 MHz,MeOD-d₄) □: 1.47-1.62 (m, 3 H), 1.63-1.85 (m, 3 R m/z 435({(1R,3S)-3-[3- and H), 1.85-1.98 (m, 4 H), 1.98-2.09 (m, 2 H),2.09-2.33 (m, 1 (M + H)⁺ (trifluoromethyl)-1,2,4- 138 H), 2.35 (s, 3 H),2.35-2.68 (m, 1 H), 2.79-2.91 (m, 1 H), 3.54- (ES⁺), at oxadiazol-5-yl]3.84 (m, 3 H), 6.83 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 4.19min, cyclopentyl}amino)spiro[ H), 7.57 (s, 1 H). NH not observed. UVactive cyclohexane-1,3′-indol]- 2′(1′ H)-one 24-3 Isomer 1: 6′-methyl-4-68 l (400 MHz, MeOD-d4) □: 1.29 (s, 1 H), 1.59-1.77 (m, 1 H), 1.73- Rm/z 381 {[(1R,3S)-3-(3-methyl- and 1.81 (m, 4 H), 1.81-1.92 (m, 3 H),2.00-2.20 (m, 5 H), 2.30 (M + H)⁺ 1,2,4-oxadiazol-5-yl) 126 (s, 3 H),2.33 (s, 3 H), 2.49 (dt, J = 13.6, 7.0 Hz, 1 H), 2.71- (ES⁺), atcyclopentyl]amino}spiro 2.81 (m, 1 H), 3.32-3.53 (m, 2 H), 6.70 (s, 1H), 6.82 (d, J = 7.7 3.41 min, [cyclohexane-1,3′-indol]- Hz, 1 H), 7.08(d, J = 7.7 Hz, 1 H). NH not observed. UV active 2′(1′ H)-one 25-1Isomer 1: 4-[6-(3-ethyl- 65 l (400 MHz, CDCl₃) □: 1.33 (t, J = 7.6 Hz, 3H), 1.49-1.61 (m, 2 E m/z 393 1,2,4-oxadiazol-5-yl)-2- and H), 1.62-1.79(m, 2 H), 1.82-1.95 (m, 4 H), 2.14-2.25 (m, 1 (M + H)⁺azaspiro[3.3]hept-2-yl] 140 H), 2.56-2.70 (m, 4 H), 2.76 (q, J = 7.8 Hz,2 H), 3.28 (s, 2 H), (ES⁺), at spiro[cyclohexane-1,3′- 3.38 (s, 2 H),3.57-3.68 (m, 1 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.98 3.77 min,indol]-2′(1′H)-one (t, J = 7.6 Hz, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.60(d, J = 7.4 Hz, UV active 1 H), 8.08 (br. s., 1 H). 26-1 Isomer 2:5′-methyl-4-[2- 70 c (400 MHz, MeOD-d₄) □: 1.55 (d, J = 10.7 Hz, 2 H),1.80-1.96 R m/z 407 (3-methyl-1,2,4- and (m, 4 H), 2.01 (t, J = 7.2 Hz,2 H), 2.06-2.17 (m, 3 H), 2.34 (s, 2 × (M + H)⁺ oxadiazol-5-yl)-6- 133 3H), 2.42-2.53 (m, 2 H), 2.61 (t, J = 10.5 Hz, 2 H), 2.78 (t, J = (ES⁺),at azaspiro[3.4]oct-6-yl] 7.1 Hz, 2 H), 2.98 (s, 2 H), 3.65-3.77 (m, 1H), 6.82 (d, J = 3.11 min, spiro[cyclohexane-1,3′- 7.9 Hz, 1 H), 7.05(d, J = 8.0 Hz, 1 H), 7.61 (s, 1 H). NH not UV active indol]-2′(1′H)-oneobserved. 26-2 Isomer 1: 5′-methoxy-4- 80 c (400 MHz, MeOD-d₄) □:1.54-1.64 (m, 2 H), 1.76-1.96 (m, 4 S m/z 423 [2-(3-methyl-1,2,4- andH), 2.02 (t, J = 7.3 Hz, 1 H), 2.05-2.15 (m, 2 H), 2.15-2.21 (m, (M +H)⁺ oxadiazol-5-yl)-6- 133 1 H), 2.28-2.38 (m, 3 H), 2.47-2.65 (m, 4 H),2.75-2.95 (m, (ES⁺), at azaspiro[3.4]oct-6- 4 H), 2.99 (s, 1 H),3.63-3.83 (m, 4 H), 6.78-6.90 (m, 2 H), 3.00 min,yl]spiro[cyclohexane-1,3′- 7.36 (dd, J = 9.5, 2.3 Hz, 1 H). NH notobserved. UV active indol]-2′(1′H)-one 26-2 Isomer 3: 5′-methoxy-4- 80 c(400 MHz, MeOD-d₄) □: 1.76-1.92 (m, 4 H), 2.06-2.27 (m, 4 S m/z 423[2-(3-methyl-1,2,4- and H), 2.34 (s, 3 H), 2.36 (d, J = 12.1 Hz, 1 H),2.43-2.51 (m, 5 H), (M + H)⁺ oxadiazol-5-yl)-6- 133 2.75-2.90 (m, 5 H),3.68-3.82 (m, 4 H), 6.69-6.85 (m, 3 H). (ES⁺), at azaspiro[3.4]oct-6-yl]NH not observed. 3.29 min, spiro[cyclohexane-1,3′- UV activeindol]-2′(1′H)-one 26-3 Isomer 1: 4-[2-(3-ethyl- 65 l (400 MHz, CDCl₃)□: 1.27-1.37 (m, 3 H), 1.64-2.02 (m, 7 H), E m/z 4071,2,4-oxadiazol-5-yl)-6- and 2.00-2.15 (m, 3 H), 2.20-2.33 (m, 1 H),2.40-2.58 (m, 4 H), (M + H)⁺ azaspiro[3.4]oct-6-yl] 141 2.64-2.89 (m, 6H), 3.56-3.72 (m, 1 H), 6.92 (d, J = 7.8 Hz, 1 (ES⁺), atspiro[cyclohexane-1,3′- H), 6.99 (td, J = 7.6, 5.0 Hz, 1 H), 7.17-7.27(m, 1 H), 7.59 (d, J = 4.02 min, indol]-2′(1′H)-one 7.6 Hz, 1 H), 8.44(s, 1 H). UV active 27-1 Isomer 2: 4-({[2-(3-ethyl- 12 l (400 MHz,CDCl₃) □: 1.12 (ddd, J = 8.6, 6.4, 4.7 Hz, 1 H), 1.30 E m/z 3511,2,4-oxadiazol-5-yl) and (t, J = 7.6 Hz, 3 H), 1.42 (dt, J = 9.2, 4.8Hz, 1 H), 1.72-1.92 (M + H)⁺ cyclopropyl]methyl} 143 (m, 5 H), 1.96-2.08(m, 3 H), 2.24-2.36 (m, 3 H), 2.61 (dd, J = (ES⁺), at amino)-1- 12.4,6.8 Hz, 1 H), 2.64-2.75 (m, 3 H), 2.95-3.05 (m, 1 H), 4.52 min,phenylcyclohexanecarbonitrile 7.25-7.35 (m, 1 H), 7.39 (dd, J = 8.6, 6.8Hz, 2 H), 7.44-7.54 UV active (m, 2 H). 28-1 Isomer 2: 1-(5- 27 c (400MHz, MeOD-d₄) □: 1.48-1.85 (m, 4 H), 1.86-2.10 (m, 5 R m/z 424fluoropyridin-2-yl)-4- and H), 2.17-2.40 (m, 2 H), 2.45-2.60 (m, 3 H),2.91-2.97 (m, 1 (M + H)⁺ ({(1R,3S)-3-[3- 138 H), 3.29-3.33 (m, 1 H),3.34-3.44 (m, 1 H), 3.52-3.77 (m, 1 (ES⁺), at (trifluoromethyl)-1,2,4-H), 7.61-7.76 (m, 2 H), 8.50 (t, J = 2.6 Hz, 1 H). 4.70 min,oxadiazol-5-yl] UV active cyclopentyl}amino) cyclohexanecarbonitrile28-2 Isomer 2: 1-(5- 43 c (400 MHz, MeOD-d₄) □: 1.64-1.71 (m, 5 H),1.85-2.05 (m, 5 R m/z 420 methylpyridin-2-yl)-4- and H), 2.08-2.28 (m, 2H), 2.30-2.40 (m, 4 H), 2.40-2.56 (m, 2 (M + H)⁺ ({(1R,3S)-3-[3- 138 H),2.90-2.98 (m, 1 H), 3.29-3.50 (m, 1 H), 3.50-3.76 (m, 1 (ES⁺), at(trifluoromethyl)-1,2,4- H), 7.56 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.4Hz, 1 H), 8.44 (s, 1 H). 4.98 min, oxadiazol-5-yl] UV activecyclopentyl}amino) cyclohexanecarbonitrile

BIOLOGICAL ACTIVITY Example A

Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M1, M3 (Gq/11 coupled) and M2, M4receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M1, M2, M3 or M4 receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight. Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

The results are a range of examples are set out in Table 4 below.

For each example at least two diastereomers exist which, when indicated,have been separated, and assigned based on their retention time onanalytical LCMS. Analytical data for all active isomers is reported inTable 3.

TABLE 4 Muscarinic Activity pEC₅₀ M1 pEC₅₀ M2 pEC₅₀ M3 pEC₅₀ M4 (% Emax(% Emax (% Emax (% Emax Ex. No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh8.33 (102) 7.82 (105) 8.12 (115) 8.09 (110)  1-1 Isomer 2 7.29 (117)<4.7 (3) <4.7 (18) <4.7 (18)  1-2 Isomer 2 6.68 (102) <4.7 (23) <4.7 (1)6.13 (52)  1-3 Isomer 2 7.51 (119) <4.7 (0) <4.7 (1) <4.7 (13)  1-4Isomer 2 7.45 (98)  <4.7 (3) <4.7 (8) <4.7 (7)  1-5 Isomer 2 6.94 (125)<4.7 (5) <4.7 (33) <4.7 (46)  1-6 Isomer 2 6.64 (116) NT NT 5.75 (49) 1-8 Isomer 2  6.6 (120) NT NT <4.7 (0)  1-9 Isomer 2 7.56 (99)  <4.7(6) <4.7 (2) <4.7 (12) 1-10 Isomer 2 7.55 (106) <4.7 (6) <4.7 (9) <4.7(24) 1-11 Isomer 2 6.83 (99)  <4.7 (0) <4.7 (1) <4.7 (9) 1-14 Isomer 26.91 (89)  <4.7 (2) <4.7 (0) <4.7 (32) 1-15 Isomer 2 6.57 (39)  NT NT<4.7 (7) 1-20 Isomer 2 6.83 (78)  <4.7 (0) <4.7 (0) <4.7 (19) 1-21Isomer 2 6.96 (64)  <4.7 (1) <4.7 (5) <4.7 (15)  2-1 isomer 1 7.13 (74) <4.7 (2) <4.7 (4) <4.7 (10)  2-2 isomer 1 6.80 (103) NT NT 6.06 (84) 2-3 isomer 1 7.11 (32)  NT NT <4.7 (1)  2-4 isomer 1 7.18 (65)  <4.8(3) <4.8 (11) <4.8 (11)  2-5 isomer 1 8.11 (49)  <4.7 (13) <4.7 (15)<4.8 (5)  2-6 isomer 1 6.73 (66)  <4.7 (11) <4.7 (16) 7.22 (54)  2-7isomer 2 7.28 (89)  <4.7 (5) <4.7 (2) <4.7 (16)  2-7 isomer 1 5.75 (35) NT NT <4.7 (1)  2-8 isomer 1 7.03 (59)  NT NT <4.7 (10)  2-9 isomer 16.55 (77)  NT NT <4.7 51) 2-10 isomer 1 8.10 (64)  <4.7 (27) <4.7 (4)<4.7 (39) 2-14 isomer 2 6.93 (77)  NT NT <4.7 56) 2-17 isomer 1 7.25(48)  <4.7 (7) <4.7 (7) <4.7 (18) 2-18 isomer 1 6.83 (122) <4.7 (21)<4.7 (11) 6.76 (141) 2-19 isomer 1 5.68 (63)  NT NT <4.7 (19) 2-20isomer 1 6.43 (32)  NT NT <4.7 (16) 2-21 isomer 2 6.33 (58)  NT NT 6.61(86)  3-2 mixture of isomers 7.60 (96)  <4.7 (7) <4.7 (46) 7.13 (76) 3-3 mixture of isomers 8.01 (101) <4.7 (38) <4.7 (35) 7.20 (85)  3-4mixture of isomers 6.53 (86)  <4.7 (12) <4.7 (40) 6.08 (46)  3-5 mixtureof isomers 7.08 (101) <4.7 (5) <4.7 (36) 6.51 (47)  3-6 mixture ofisomers 8.02 (105) <4.7 (11) <4.7 (38) 7.00 (62)  3-7 mixture of isomers6.41 (101) <4.7 (35) <4.7 (34) 5.77 (48)  3-8 mixture of isomers 7.45(106) <4.7 (18) <4.7 (7) 6.98 (62)  3-9 mixture of isomers 6.94 (98) <4.7 (33) <4.7 (0) <4.7 (2) 3-11 mixture of isomers 7.14 (97)  <4.7 (43)<4.7 (15) 6.41 (99) 3-12 mixture of isomers 6.81 (116) <4.7 (5) <4.7 (3)5.97 (48) 3-16 mixture of isomers 8.18 (103) <4.7 (10) <4.7 (39) 6.90(90) 3-17 Isomer 1 8.52 (92)  <4.7 (0) <4.7 (0) 7.14 (80) 3-19 Isomer 27.52 (101) <4.7 (5) <4.7 (6) 5.76 (39) 3-20 Isomer 2 7.94 (139) <4.7(27) <4.7 (2) <4.7 (7) 3-21 mixture of isomers 6.14 (90)  <4.7 (3) <4.7(2) <4.7 (53) 3-26 mixture of isomers 7.39 (85)  NT NT NT 3-28 mixtureof isomers 6.11 (116) <4.7 (15) <4.7 (7) 6.61 (91) 3-29 mixture ofisomers 6.27 (75)  <4.7 (3) <4.7 (3) 6.70 (68) 3-30 Isomer 1 6.53 (104)<4.7 (6) <4.7 (0) 6.64 (72) 3-31 Isomer 1 7.71 (91)  <4.7 (8) <4.7 (0)5.59 (52) 3-32 Isomer 1 7.65 (106) <4.7 (2) <4.7 (0) 6.12 (30)  4-3isomer 2 6.10 (57)  <4.7 (3) <4.7 (2) <4.7 (20)  4-4 isomer 2 6.59 (48) NT NT <4.7 (12)  4-6 isomer 1 6.24 (85)  NT NT 5.49 (26)  4-6 isomer 27.44 (130) <4.8 (39) <4.8 (17) 7.12 (116)  4-7 isomer 1 7.35 (115) <4.7(16) <4.7 (20) 5.27 (100)  4-8 isomer 1 5.96 (67)  NT NT 6.42 (52)  4-8isomer 2 6.69 (97)  <4.7 (17) <4.7 (9) 7.01 (95) 4-11 isomer 2 6.88(107) <4.7 (9) <4.7 (2) 6.51 (55) 4-12 isomer 1 7.05 (107) <4.7 (3) <4.7(34) <4.7 (10) 4-13 isomer 2 6.02 (38)  NT NT 6.46 (39) 4-14 isomer 16.01 (76)  NT NT <4.7 (24) 4-16 isomer 1 6.05 (60)  NT NT <4.7 (5) 4-17isomer 2 6.36 (89)  NT NT <4.7 (19) 4-19 isomer 1 5.17 (104) NT NT 6.49(97) 4-24 isomer 1 6.09 (75)  NT NT 6.50 (61)  5-1 Isomer 2 7.18 (115)<4.7 (8) <4.7 (7) 6.29 (26)  6-2-Isomer 2 7.23 (129) <4.7 (0) <4.7 (12)7.27 (49)  7-1 isomer 1 6.59 (112) NT NT 6.80 (26)  7-1 isomer 2 6.31(68)  NT NT 6.55 (20)  7-2 isomer 1 7.12 (122) <4.7 (37) <4.7 (3) 6.77(32)  7-2 isomer 2 6.41 (66)  NT NT <4.7 (10)  9-1 Isomer 1 6.67 (84) <4.7 (7) <4.7 (0) <4.7 (14) 10-1 mixture of isomers 7.41 (39)  NT NT<4.7 (8) 11-1 Isomer 2 6.56 (105) <4.7 (1) <4.7 (3) <4.7 (19) 12-1isomer 1 7.86 (109) <4.7 (18) <4.7 (1) 8.32 (82) 12-2 isomer 1 7.59(65)  <4.7 (27) <4.7 (0) 7.97 (48) 13-1 Isomer 2 9.35 (121) <4.7 (21)<4.7 (7) 9.84 (121) 14-1 Isomer 2 7.05 (106) <4.7 (0) <4.7 (1) 6.45 (63)15-1 Isomer 2 6.81 (117) <4.7 (14) <4.7 (6) 6.84 (21) 17-1 Isomer 2 7.01(111) <4.7 (9) <4.7 (9) 6.60 (61) 19-1 Isomer 2 5.76 (45)  <4.7 (21)<4.7 (8) 6.65 (83) 19-2 Isomer 2 6.72 (118) 5.62 (35) <4.7 (5) 6.86 (96)20-1 Isomer 2 6.66 (78)  <4.7 (61) <4.7 (30) 6.90 (58) 21-2 Isomer 37.14 (77)  <4.7 (16) <4.7 (15) 7.21 (58) 21-3 Isomer 3 6.25 (51)  NT NT<4.7 (15) 21-3 Isomer 4 6.79 (80)  NT NT 7.16 (75) 21-4 Isomer 4 5.67(47)  NT NT 6.51 (68) 21-5 Isomer 1 <4.7 (18)  NT NT 5.97 (55) 21-5Isomer 2 4.84 (82)  NT NT 5.90 (51) 22-1 Isomer 1 6.64 (83)  <4.7 (11)<4.7 (11) 6.40 (47) 22-2 Isomer 1 7.15 (55)  <4.7 (12) <4.7 (21) 6.27(42) 22-3 Isomer 1 6.91 (51)  <4.7 (17) <4.7 (59) 6.85 (40) 22-4 Isomer1 7.10 (76)  <4.7 (20) <4.7 (17) 6.66 (39) 23-1 Isomer 1 6.46 (113) NT<4.7 (8) 6.60 (78) 24-1 Isomer 1 6.66 (89)  <4.7 (16) <4.7 (23) 6.98(62) 24-2 Isomer 1 7.20 (62)  5.12 (38) 4.80 (100) 5.36 (85) 24-3 Isomer1 6.45 (81)  NT NT 6.38 (39) 25-1 Isomer 1 6.21 (43)  <4.7 (13) <4.7 (6)6.81 (70) 26-1 Isomer 2 7.82 (74)  <4.7 (22) <4.7 (7) 7.39 (50) 26-2Isomer 1 7.79 (38)  <4.7 (6) <4.7 (4) 7.09 (35) 26-2 Isomer 3 6.65 (51) NT NT <4.7 (14) 26-3 Isomer 1 7.03 (31)  <4.7 (11) <4.7 (19) 7.54 (72)27-1 Isomer 2 6.27 (92)  NT NT 6.75 (84) 28-1 Isomer 2 6.01 (59)  NT NT6.08 (45) 28-2 Isomer 2 5.46 (40)  NT NT 6.02 (55) NT —Not tested

Example B

Pharmaceutical Formulations

(i) Tablet Formulation

A tablet composition containing a compound of the formula (1) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (1) with 100 mg lactose and optionally 1% by weight of magnesiumstearate and filling the resulting mixture into standard opaque hardgelatin capsules.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

The invention claimed is:
 1. A compound of formula (1):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Q¹ is N; Q² is N or CH; X¹ is a saturated hydrocarbon group, optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of F, Cl, Br, I, CN, OH, NH₂, and C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 F; X²is a saturated hydrocarbon group, optionally substituted with 1, 2, or 3substituents independently selected from the group consisting of F, Cl,Br, I, CN, OH, NH₂, and C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, 4, 5, or 6 F; W is -Q³C(O)YCH₂R⁴; Q³ is abond; Y is —O—; R⁴ is H or a C₁₋₆ non-aromatic hydrocarbon group,wherein the C₁₋₆ non-aromatic hydrocarbon group is optionallysubstituted with 1, 2, 3, 4, 5, or 6 F, and further wherein 1 or 2 —CH₂—groups of the C₁₋₆ non-aromatic hydrocarbon group may be optionally andindependently replaced by a heteroatom selected from the groupconsisting of N, O, and S; Q⁴ is a 6-membered carbocyclic aromatic ring,wherein the 6-membered carbocyclic aromatic ring is optionallysubstituted with 1 or more independently selected Q⁶ substituents; or Q⁴is a 5- or 6-membered heterocyclic aromatic ring, wherein the 5- or6-membered heterocyclic aromatic ring contains 1, 2, or 3 heteroatomsindependently selected from the group consisting of N, O, and S, andfurther wherein the 5- or 6-membered heterocyclic aromatic ring isoptionally substituted with 1 or more independently selected Q⁶substituents; Q⁵ is H, F, CN, OH, NH₂, or a C₁₋₉ non-aromatichydrocarbon group, wherein the C₁₋₉ non-aromatic hydrocarbon group isoptionally substituted with 1, 2, 3, 4, 5, or 6 F, and further wherein1, 2, or 3 —CH₂— groups of the C₁₋₉ non-aromatic hydrocarbon group maybe optionally and independently replaced by a heteroatom selected fromthe group consisting of 0 and S; each Q⁶ is independently F, Cl, Br, I,CN, OH, NH₂, or a C₁₋₁₀ non-aromatic hydrocarbon group, wherein eachC₁₋₁₀ non-aromatic hydrocarbon group is optionally and independentlysubstituted with 1, 2, 3, 4, 5, or 6 F, and further wherein 1, 2, or 3—CH₂— groups of the C₁₋₁₀ non-aromatic hydrocarbon group may beoptionally and independently replaced by a heteroatom selected from thegroup consisting of N, O, and S; V is a bond; R⁵ is F or a C₁₋₄hydrocarbon group; and p is 0, 1, or 2; with the proviso that X¹ and X²together contain a total of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons.
 2. Thecompound according to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R⁴ is H, CH₃, CH₂F, C≡CH, or C≡CCH₃. 3.The compound according to claim 1, or a pharmaceutically acceptable saltor stereoisomer thereof, wherein R⁴ is CH₃.
 4. The compound according toclaim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein Q⁴ is phenyl, imidazolyl, thienyl, or pyridyl, wherein thephenyl, imidazolyl, thienyl, and pyridyl are each optionally substitutedwith 1 or more independently selected Q⁶ substituents.
 5. The compoundaccording to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Q⁵ is H, CN, or C(O)OCH₃.
 6. The compoundaccording to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Q⁵ is CN.
 7. The compound according toclaim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein each Q⁶ is independently F, Cl, Br, I, CH₃, CF₃, CH₂CH₃, OCH₃,or OCH₂CH₃.
 8. The compound according to claim 1, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein: (a) p is 0; or (b) pis 1; and R⁵ is F or CH₃.
 9. The compound according to claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, wherein

is A, B, C, L, M, N, O, P, or DD:

where “a” indicates the point of attachment to the cyclohexane ring and“b” indicates the point of attachment to the W group.
 10. The compoundaccording to claim 1, wherein the compound is of formula (4):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R⁹ is H, F, or OH.
 11. The compound according to claim 1, or astereoisomer thereof, wherein the compound, or stereoisomer thereof, isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound according to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof.
 13. A compound selected from the group consistingof:

or a pharmaceutically acceptable salt or stereoisomer thereof.